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Alves-Hanna FS, Silva FRP, Pereira DS, Leal ALAB, Magalhães-Gama F, Costa AG. Association between the IL1B-511 C>T polymorphism and the risk of hematologic malignancies: data from a meta-analysis. Cancer Biol Ther 2024; 25:2382503. [PMID: 39039694 PMCID: PMC11268255 DOI: 10.1080/15384047.2024.2382503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 07/16/2024] [Indexed: 07/24/2024] Open
Abstract
The relationship between the IL1B-511C>T (rs16944) polymorphism and the risk of developing hematologic malignancies remains controversial. Thus, we performed a meta-analysis to evaluate the association between IL1B-511C>T polymorphism and the risk of developing hematologic malignancies. A comprehensive search was conducted to identify all eligible studies on IL1B-511C>T polymorphism and hematologic malignancies. Twelve case-control studies, with 2,896 cases and 3,716 controls, were selected for the analysis. The overall data failed to indicate a significant association between IL1B-511C>T polymorphism and the risk of hematologic malignancies (OR:1.06, 95% Confidence Interval [CI]: 0.93-1.22). Moreover, non-significant associations were observed in a stratified analysis according to neoplasm type (multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma), ethnicity (European and Asian), and Hardy-Weinberg equilibrium. In summary, our results suggest that there is no association between the IL1B-511C>T polymorphism and the risk of hematologic malignancies. As such, further large-scale studies are needed to confirm our findings.
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Affiliation(s)
- Fabíola Silva Alves-Hanna
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Brazil
| | - Felipe Rodolfo Pereira Silva
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Brazil
- Faculdade de Medicina, Universidade Federal do Pará (UFPA), Altamira, Brazil
| | - Daniele Sá Pereira
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Brazil
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Brazil
| | | | - Fábio Magalhães-Gama
- Programa de Pós-Graduação em Ciências da Saúde, Instituto René Rachou – Fundação, Oswaldo Cruz (FIOCRUZ) Minas, Belo Horizonte, Brazil
| | - Allyson Guimarães Costa
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Brazil
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Brazil
- Escola de Enfermagem de Manaus, Universidade Federal do Amazonas (UFAM), Manaus, Brazil
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Liang MX, Chen Y, He Y, He YH. Journey to diagnosis: An unfinished exploration of IgG4-related sclerosing cholangitis. World J Clin Cases 2024; 12:6608-6612. [PMID: 39600477 PMCID: PMC11514334 DOI: 10.12998/wjcc.v12.i33.6608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/19/2024] [Accepted: 08/23/2024] [Indexed: 09/27/2024] Open
Abstract
IgG4-related sclerosing cholangitis (IgG4-SC) is an inflammatory disease that leads to bile duct stricture, characterized by the infiltration of IgG4-positive plasma cells into the bile duct wall, thickening of the bile duct wall, and narrowing of the lumen. The differential diagnosis of IgG4-SC mainly includes primary sclerosing cholangitis, cholangiocarcinoma, and pancreatic cancer. IgG4-SC is often associated with autoimmune pancreatitis and can be accurately diagnosed based on clinical diagnostic criteria. However, isolated IgG4-SC is difficult to distinguish from biliary tumors. Given the significant differences in biological behavior, treatment, and prognosis between these diseases, accurately identifying isolated IgG4-SC has very important clinical significance.
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Affiliation(s)
- Ming-Xing Liang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Ya Chen
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Ya He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Yi-Huai He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
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Wu ZN, JI R, Xiao Y, Wang YD, Zhao CY. IgG4-related sclerosing cholangitis associated with essential thrombocythemia: A case report. World J Clin Cases 2024; 12:5589-5595. [PMID: 39188618 PMCID: PMC11269987 DOI: 10.12998/wjcc.v12.i24.5589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 05/05/2024] [Accepted: 06/04/2024] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND The complexity of immunoglobulin G4 (IgG4)-related diseases and their potential connection to hematologic malignancies remains unclear. This article provided a review of the diagnosis and treatment of a patient with IgG4-related sclerosing cholangitis (SC) and essential thrombocythemia (ET), along with an analysis of relevant literature to enhance comprehension of this disease. CASE SUMMARY A 56-year-old male was admitted to two hospitals with deteriorating jaundice and pruritus prior to hospitalization. Beyond our expectations, the patient was first diagnosed with IgG4-SC and ET with the Janus kinase 2 V617F mutation. Interestingly, the administration of acetate prednisone significantly resulted in improvements in both IgG4-SC and ET. Clinicians need to pay attention to immune disorders and inflammation as they contribute to the development of various disease phenotypes. CONCLUSION When IgG4-SC is suspected without histopathological evidence, diagnostic therapy and long-term regular follow-up can lead to positive treatment outcomes. Clinicians should be mindful of the potential presence of concurrent hematologic diseases in patients with immune disorders.
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Affiliation(s)
- Zhi-Nian Wu
- Department of Infectious Diseases, The Hebei Medical University Third Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Ru JI
- Department of Infectious Diseases, The Hebei Medical University Third Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Ying Xiao
- Department of Infectious Diseases, The Hebei Medical University Third Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Ya-Dong Wang
- Department of Infectious Diseases, The Hebei Medical University Third Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Cai-Yan Zhao
- Department of Infectious Diseases, The Hebei Medical University Third Hospital, Shijiazhuang 050051, Hebei Province, China
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Paes JF, Torres DG, Aquino DC, Alves EVB, Mesquita EA, Sousa MA, Fraiji NA, Passos LNM, Abreu RS, Silva GAV, Tarragô AM, de Souza Mourão LP. Exploring hematological alterations and genetics linked to SNV rs10974944 in myeloproliferative neoplasms among Amazon patients. Sci Rep 2024; 14:9389. [PMID: 38654055 PMCID: PMC11039700 DOI: 10.1038/s41598-024-60090-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 04/18/2024] [Indexed: 04/25/2024] Open
Abstract
BCR::ABL1-negative myeloproliferative neoplasms are hematopoietic disorders characterized by panmyelosis. JAK2 V617F is a frequent variant in these diseases and often occurs in the 46/1 haplotype. The G allele of rs10974944 has been shown to be associated with this variant, specifically its acquisition, correlations with familial cases, and laboratory alterations. This study evaluated the association between the 46/1 haplotype and JAK2 V617F in patients with myeloproliferative neoplasms in a population from the Brazilian Amazon. Clinical, laboratory and molecular sequencing analyses were considered. Carriers of the G allele of rs10974944 with polycythemia vera showed an increase in mean corpuscular volume and mean corpuscular hemoglobin, while in those with essential thrombocythemia, there was an elevation in red blood cells, hematocrit, and hemoglobin. Associations were observed between rs10974944 and the JAK2 V617F, in which the G allele (OR 3.4; p < 0.0001) and GG genotype (OR 4.9; p = 0.0016) were associated with JAK2 V617F + and an increase in variant allele frequency (GG: OR 15.8; p = < 0.0001; G: OR 6.0; p = 0.0002). These results suggest an association between rs10974944 (G) and a status for JAK2 V617F, JAK2 V617F + _VAF ≥ 50%, and laboratory alterations in the erythroid lineage.
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Affiliation(s)
- Jhemerson F Paes
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
| | - Dania G Torres
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
| | - Deborah C Aquino
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
| | - Emanuela V B Alves
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
| | - Erycka A Mesquita
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
| | - Miliane A Sousa
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
| | - Nelson Abrahim Fraiji
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (FHEMOAM), Manaus, AM, 69050-002, Brazil
| | - Leny N M Passos
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (FHEMOAM), Manaus, AM, 69050-002, Brazil
| | - Rosângela S Abreu
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (FHEMOAM), Manaus, AM, 69050-002, Brazil
| | - George A V Silva
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
| | - Andréa M Tarragô
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (FHEMOAM), Manaus, AM, 69050-002, Brazil
| | - Lucivana P de Souza Mourão
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, AM, 69850-000, Brazil.
- Escola Superior em Ciências da Saúde (ESA/UEA), Av. Carvalho Leal, 1777 - Cachoeirinha, Manaus, AM, 69065-001, Brazil.
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Boccatonda A, Gentilini S, Zanata E, Simion C, Serra C, Simioni P, Piscaglia F, Campello E, Ageno W. Portal Vein Thrombosis: State-of-the-Art Review. J Clin Med 2024; 13:1517. [PMID: 38592411 PMCID: PMC10932352 DOI: 10.3390/jcm13051517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 03/03/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
Background: Portal vein thrombosis (PVT) is a rare disease with an estimated incidence of 2 to 4 cases per 100,000 inhabitants. The most common predisposing conditions for PVT are chronic liver diseases (cirrhosis), primary or secondary hepatobiliary malignancy, major infectious or inflammatory abdominal disease, or myeloproliferative disorders. Methods: PVT can be classified on the basis of the anatomical site, the degree of venous occlusion, and the timing and type of presentation. The main differential diagnosis of PVT, both acute and chronic, is malignant portal vein invasion, most frequently by hepatocarcinoma, or constriction (typically by pancreatic cancer or cholangiocarcinoma). Results: The management of PVT is based on anticoagulation and the treatment of predisposing conditions. The aim of anticoagulation in acute thrombosis is to prevent the extension of the clot and enable the recanalization of the vein to avoid the development of complications, such as intestinal infarction and portal hypertension. Conclusions: The treatment with anticoagulant therapy favors the reduction of portal hypertension, and this allows for a decrease in the risk of bleeding, especially in patients with esophageal varices. The anticoagulant treatment is generally recommended for at least three to six months. Prosecution of anticoagulation is advised until recanalization or lifelong if the patient has an underlying permanent pro-coagulant condition that cannot be corrected or if there is thrombosis extending to the mesenteric veins.
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Affiliation(s)
- Andrea Boccatonda
- Internal Medicine, Bentivoglio Hospital, Azienda Unità Sanitaria Locale (AUSL) Bologna, 40010 Bentivoglio, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Simone Gentilini
- Internal Medicine Department, IRCCS Azienda Ospedaliero-Universitaria Policlinico di Sant’Orsola, 40138 Bologna, Italy; (S.G.); (E.Z.)
| | - Elisa Zanata
- Internal Medicine Department, IRCCS Azienda Ospedaliero-Universitaria Policlinico di Sant’Orsola, 40138 Bologna, Italy; (S.G.); (E.Z.)
| | - Chiara Simion
- General Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy (E.C.)
| | - Carla Serra
- Interventional, Diagnostic and Therapeutic Ultrasound Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Paolo Simioni
- General Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy (E.C.)
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Elena Campello
- General Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy (E.C.)
| | - Walter Ageno
- Research Center on Thromboembolic Diseases and Antithrombotic Therapies, Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy
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Pescia C, Lopez G, Cattaneo D, Bucelli C, Gianelli U, Iurlo A. The molecular landscape of myeloproliferative neoplasms associated with splanchnic vein thrombosis: Current perspective. Leuk Res 2024; 136:107420. [PMID: 38016412 DOI: 10.1016/j.leukres.2023.107420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 10/30/2023] [Accepted: 11/03/2023] [Indexed: 11/30/2023]
Abstract
BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are classically represented by polycythemia vera, essential thrombocythemia, and primary myelofibrosis. BCR::ABL1-negative MPNs are significantly associated with morbidity and mortality related to an increased risk of thrombo-hemorrhagic events. They show a consistent association with splanchnic vein thrombosis (SVT), either represented by the portal, mesenteric or splenic vein thrombosis, or Budd-Chiari Syndrome. SVT is also a frequent presenting manifestation of MPN. MPNs associated with SVT show a predilection for younger women, high association with JAK2V617F mutation, low JAK2V617F variant allele frequency (generally <10 %), and low rates of CALR, MPL, or JAK2 exon 12 mutations. Next-Generation Sequencing techniques have contributed to deepening our knowledge of the molecular landscape of such cases, with potential diagnostic and prognostic implications. In this narrative review, we analyze the current perspective on the molecular background of MPN associated with SVT, pointing as well future directions in this field.
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Affiliation(s)
- Carlo Pescia
- Unit of Anatomic Pathology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
| | - Gianluca Lopez
- Unit of Anatomic Pathology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy
| | - Daniele Cattaneo
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Cristina Bucelli
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Umberto Gianelli
- Department of Health Sciences, University of Milan, Milan, Italy; Unit of Anatomic Pathology, ASST Santi Paolo e Carlo, Milan, Italy
| | - Alessandra Iurlo
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Skov V, Thomassen M, Kjaer L, Larsen MK, Knudsen TA, Ellervik C, Kruse TA, Hasselbalch HC. Whole blood transcriptional profiling reveals highly deregulated atherosclerosis genes in Philadelphia-chromosome negative myeloproliferative neoplasms. Eur J Haematol 2023; 111:805-814. [PMID: 37640394 DOI: 10.1111/ejh.14081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a huge comorbidity burden, including an increased risk of cardiovascular diseases. Recently, chronic inflammation has been suggested to be the driving force for clonal evolution and disease progression in MPN but also potentially having an impact upon the development of accelerated (premature) atherosclerosis. OBJECTIVES Since chronic inflammation, atherosclerosis, and atherothrombosis are prevalent in MPNs and we have previously shown oxidative stress genes to be markedly upregulated in MPNs, we hypothesized that genes linked to development of atherosclerosis might be highly deregulated as well. METHODS Using whole blood gene expression profiling in patients with essential thrombocythemia (ET; n = 19), polycythemia vera (PV; n = 41), or primary myelofibrosis (PMF; n = 9), we herein for the first time report aberrant expression of several atherosclerosis genes. RESULTS Of 84 atherosclerosis genes, 45, 56, and 46 genes were deregulated in patients with ET, PV, or PMF, respectively. Furthermore, BCL2L1, MMP1, PDGFA, PTGS1, and THBS4 were progressively significantly upregulated and BCL2 progressively significantly downregulated from ET over PV to PMF (all FDR <0.05). CONCLUSIONS We have for the first time shown massive deregulation of atherosclerosis genes in MPNs, likely reflecting the inflammatory state in MPNs in association with in vivo activation of leukocytes, platelets, and endothelial cells being deeply involved in the atherosclerotic process.
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Affiliation(s)
- Vibe Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Lasse Kjaer
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | | | - Trine A Knudsen
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Christina Ellervik
- Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
| | - Torben A Kruse
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
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Hermouet S. Mutations, inflammation and phenotype of myeloproliferative neoplasms. Front Oncol 2023; 13:1196817. [PMID: 37284191 PMCID: PMC10239955 DOI: 10.3389/fonc.2023.1196817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/09/2023] [Indexed: 06/08/2023] Open
Abstract
Knowledge on the myeloproliferative neoplasms (MPNs) - polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) - has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs: JAK2V617F, observed in PV, ET and PMF; and the MPL and CALR mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations (ASXL1, DNMT3A, TET2, others), have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs (JAK inhibitors, interferons, hydroxyurea, anagrelide, azacytidine, combinations of those), some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies.
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Affiliation(s)
- Sylvie Hermouet
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, Nantes, France
- Laboratoire d'Hématologie, CHU Nantes, Nantes, France
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Hasselbalch H, Skov V, Kjær L, Larsen MK, Knudsen TA, Lucijanić M, Kusec R. Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives. Cancers (Basel) 2022; 14:5495. [PMID: 36428587 PMCID: PMC9688061 DOI: 10.3390/cancers14225495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/25/2022] [Accepted: 11/02/2022] [Indexed: 11/12/2022] Open
Abstract
About 30 years ago, the first clinical trials of the safety and efficacy of recombinant interferon-α2 (rIFN-α2) were performed. Since then, several single-arm studies have shown rIFN-α2 to be a highly potent anticancer agent against several cancer types. Unfortunately, however, a high toxicity profile in early studies with rIFN-α2 -among other reasons likely due to the high dosages being used-disqualified rIFN-α2, which was accordingly replaced with competitive drugs that might at first glance look more attractive to clinicians. Later, pegylated IFN-α2a (Pegasys) and pegylated IFN-α2b (PegIntron) were introduced, which have since been reported to be better tolerated due to reduced toxicity. Today, treatment with rIFN-α2 is virtually outdated in non-hematological cancers, where other immunotherapies-e.g., immune-checkpoint inhibitors-are routinely used in several cancer types and are being intensively investigated in others, either as monotherapy or in combination with immunomodulatory agents, although only rarely in combination with rIFN-α2. Within the hematological malignancies, rIFN-α2 has been used off-label for decades in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs)-i.e., essential thrombocythemia, polycythemia vera, and myelofibrosis-and in recent years rIFN-α2 has been revived with the marketing of ropeginterferon-α2b (Besremi) for the treatment of polycythemia vera patients. Additionally, rIFN-α2 has been revived for the treatment of chronic myelogenous leukemia in combination with tyrosine kinase inhibitors. Another rIFN formulation-recombinant interferon-β (rIFN-β)-has been used for decades in the treatment of multiple sclerosis but has never been studied as a potential agent to be used in patients with MPNs, although several studies and reviews have repeatedly described rIFN-β as an effective anticancer agent as well. In this paper, we describe the rationales and perspectives for launching studies on the safety and efficacy of rIFN-β in patients with MPNs.
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Affiliation(s)
- Hans Hasselbalch
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Vibe Skov
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | | | - Trine A. Knudsen
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Marko Lucijanić
- Department of Hematology, University Hospital Dubrava, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Rajko Kusec
- Department of Hematology, University Hospital Dubrava, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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10
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Paes J, Silva GAV, Tarragô AM, Mourão LPDS. The Contribution of JAK2 46/1 Haplotype in the Predisposition to Myeloproliferative Neoplasms. Int J Mol Sci 2022; 23:12582. [PMID: 36293440 PMCID: PMC9604447 DOI: 10.3390/ijms232012582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/13/2022] [Accepted: 10/15/2022] [Indexed: 11/17/2022] Open
Abstract
Haplotype 46/1 (GGCC) consists of a set of genetic variations distributed along chromosome 9p.24.1, which extend from the Janus Kinase 2 gene to Insulin like 4. Marked by four jointly inherited variants (rs3780367, rs10974944, rs12343867, and rs1159782), this haplotype has a strong association with the development of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) because it precedes the acquisition of the JAK2V617F variant, a common genetic alteration in individuals with these hematological malignancies. It is also described as one of the factors that increases the risk of familial MPNs by more than five times, 46/1 is associated with events related to inflammatory dysregulation, splenomegaly, splanchnic vein thrombosis, Budd-Chiari syndrome, increases in RBC count, platelets, leukocytes, hematocrit, and hemoglobin, which are characteristic of MPNs, as well as other findings that are still being elucidated and which are of great interest for the etiopathological understanding of these hematological neoplasms. Considering these factors, the present review aims to describe the main findings and discussions involving the 46/1 haplotype, and highlights the molecular and immunological aspects and their relevance as a tool for clinical practice and investigation of familial cases.
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Affiliation(s)
- Jhemerson Paes
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil
| | - George A. V. Silva
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (FHEMOAM), Manaus 69050-001, AM, Brazil
- Fundação Oswaldo Cruz–Instituto Leônidas e Maria Deane (Fiocruz), Manaus 69027-070, AM, Brazil
| | - Andréa M. Tarragô
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (FHEMOAM), Manaus 69050-001, AM, Brazil
| | - Lucivana P. de Souza Mourão
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (FHEMOAM), Manaus 69050-001, AM, Brazil
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11
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Hsu CC, Wang YH, Chen YY, Chen YJ, Lu CH, Wu YY, Yang YR, Tsou HY, Li CP, Huang CE, Chen CC. The Genomic Landscape in Philadelphia-Negative Myeloproliferative Neoplasm Patients with Second Cancers. Cancers (Basel) 2022; 14:cancers14143435. [PMID: 35884495 PMCID: PMC9316742 DOI: 10.3390/cancers14143435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/01/2022] [Accepted: 07/11/2022] [Indexed: 02/04/2023] Open
Abstract
Patients with myeloproliferative neoplasms (MPNs) are characterized by systemic inflammation. With the indolent nature of the diseases, second cancers (SCs) have emerged as a challenging issue in afflicted patients. Epidemiological studies have confirmed the excessive risk of SCs in MPNs, but little is known about their molecular basis. To explore further, we used whole exome sequencing to explore the genetic changes in the granulocytes of 26 paired MPN patients with or without SC. We noticed that MPN−SC patients harbor genomic variants of distinct genes, among which a unique pattern of co-occurrence or mutual exclusiveness could be identified. We also found that mutated genes in MPN−SC samples were enriched in immune-related pathways and inflammatory networks, an observation further supported by their increased plasma levels of TGF-β and IL-23. Noteworthily, variants of KRT6A, a gene capable of mediating tumor-associate macrophage activity, were more commonly detected in MPN−SC patients. Analysis through OncodriveCLUST disclosed that KRT6A replaces JAK2V617F as the more prominent disease driver in MPN−SC, whereas a major mutation in this gene (KRT6A c.745T>C) in our patients is linked to human carcinoma and predicted to be pathogenic in COSMIC database. Overall, we demonstrate that inflammation could be indispensable in MPN−SC pathogenesis.
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Affiliation(s)
- Chia-Chen Hsu
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
| | - Ying-Hsuan Wang
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
| | - Yi-Yang Chen
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
| | - Ying-Ju Chen
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
| | - Chang-Hsien Lu
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
- College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan
| | - Yu-Ying Wu
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
| | - Yao-Ren Yang
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
| | - Hsing-Yi Tsou
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
| | - Chian-Pei Li
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
| | - Cih-En Huang
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
- College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan
- Correspondence: (C.-E.H.); (C.-C.C.)
| | - Chih-Cheng Chen
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (C.-C.H.); (Y.-H.W.); (Y.-Y.C.); (Y.-J.C.); (C.-H.L.); (Y.-Y.W.); (Y.-R.Y.); (H.-Y.T.); (C.-P.L.)
- College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan
- Correspondence: (C.-E.H.); (C.-C.C.)
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12
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Interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms favorably impacts deregulation of oxidative stress genes and antioxidative defense mechanisms. PLoS One 2022; 17:e0270669. [PMID: 35771847 PMCID: PMC9246201 DOI: 10.1371/journal.pone.0270669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 06/14/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic inflammation is considered a major driving force for clonal expansion and evolution in the Philadelphia-negative myeloproliferative neoplasms, which include essential thrombocythemia, polycythemia vera and primary myelofibrosis (MPNs). One of the key mutation drivers is the JAK2V617F mutation, which has been shown to induce the generation of reactive oxygen species (ROS). Using whole blood gene expression profiling, deregulation of several oxidative stress and anti-oxidative defense genes has been identified in MPNs, including significant downregulation of TP53, the NFE2L2 or NRF2 genes. These genes have a major role for maintaining genomic stability, regulation of the oxidative stress response and in modulating migration or retention of hematopoietic stem cells. Therefore, their deregulation might give rise to increasing genomic instability, increased chronic inflammation and disease progression with egress of hematopoietic stem cells from the bone marrow to seed in the spleen, liver and elsewhere. Interferon-alpha2 (rIFNα) is increasingly being recognized as the drug of choice for the treatment of patients with MPNs. Herein, we report the first gene expression profiling study on the impact of rIFNα upon oxidative stress and antioxidative defense genes in patients with MPNs (n = 33), showing that rIFNα downregulates several upregulated oxidative stress genes and upregulates downregulated antioxidative defense genes. Treatment with rIFNα induced upregulation of 19 genes in ET and 29 genes in PV including CXCR4 and TP53. In conclusion, this rIFNα- mediated dampening of genotoxic damage to hematopoietic cells may ultimately diminish the risk of additional mutations and accordingly clonal evolution and disease progression towards myelofibrotic and leukemic transformation.
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13
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Bhuria V, Baldauf CK, Schraven B, Fischer T. Thromboinflammation in Myeloproliferative Neoplasms (MPN)-A Puzzle Still to Be Solved. Int J Mol Sci 2022; 23:ijms23063206. [PMID: 35328626 PMCID: PMC8954909 DOI: 10.3390/ijms23063206] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/11/2022] [Accepted: 03/15/2022] [Indexed: 02/04/2023] Open
Abstract
Myeloproliferative neoplasms (MPNs), a group of malignant hematological disorders, occur as a consequence of somatic mutations in the hematopoietic stem cell compartment and show excessive accumulation of mature myeloid cells in the blood. A major cause of morbidity and mortality in these patients is the marked prothrombotic state leading to venous and arterial thrombosis, including myocardial infarction (MI), deep vein thrombosis (DVT), and strokes. Additionally, many MPN patients suffer from inflammation-mediated constitutional symptoms, such as fever, night sweats, fatigue, and cachexia. The chronic inflammatory syndrome in MPNs is associated with the up-regulation of various inflammatory cytokines in patients and is involved in the formation of the so-called MPN thromboinflammation. JAK2-V617F, the most prevalent mutation in MPNs, has been shown to activate a number of integrins on mature myeloid cells, including granulocytes and erythrocytes, which increase adhesion and drive venous thrombosis in murine knock-in/out models. This review aims to shed light on the current understanding of thromboinflammation, involvement of neutrophils in the prothrombotic state, plausible molecular mechanisms triggering the process of thrombosis, and potential novel therapeutic targets for developing effective strategies to reduce the MPN disease burden.
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Affiliation(s)
- Vikas Bhuria
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (V.B.); (C.K.B.); (T.F.)
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Center for Health and Medical Prevention—ChaMP, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Conny K. Baldauf
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (V.B.); (C.K.B.); (T.F.)
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Burkhart Schraven
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (V.B.); (C.K.B.); (T.F.)
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Center for Health and Medical Prevention—ChaMP, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Correspondence: ; Tel.: +49-391-67-15338; Fax: +49-391-67-15852
| | - Thomas Fischer
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (V.B.); (C.K.B.); (T.F.)
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Center for Health and Medical Prevention—ChaMP, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
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14
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Bhuria V, Baldauf CK, Schraven B, Fischer T. Thromboinflammation in Myeloproliferative Neoplasms (MPN)-A Puzzle Still to Be Solved. Int J Mol Sci 2022. [PMID: 35328626 DOI: 10.3390/ijms23063206.pmid:35328626;pmcid:pmc8954909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
Myeloproliferative neoplasms (MPNs), a group of malignant hematological disorders, occur as a consequence of somatic mutations in the hematopoietic stem cell compartment and show excessive accumulation of mature myeloid cells in the blood. A major cause of morbidity and mortality in these patients is the marked prothrombotic state leading to venous and arterial thrombosis, including myocardial infarction (MI), deep vein thrombosis (DVT), and strokes. Additionally, many MPN patients suffer from inflammation-mediated constitutional symptoms, such as fever, night sweats, fatigue, and cachexia. The chronic inflammatory syndrome in MPNs is associated with the up-regulation of various inflammatory cytokines in patients and is involved in the formation of the so-called MPN thromboinflammation. JAK2-V617F, the most prevalent mutation in MPNs, has been shown to activate a number of integrins on mature myeloid cells, including granulocytes and erythrocytes, which increase adhesion and drive venous thrombosis in murine knock-in/out models. This review aims to shed light on the current understanding of thromboinflammation, involvement of neutrophils in the prothrombotic state, plausible molecular mechanisms triggering the process of thrombosis, and potential novel therapeutic targets for developing effective strategies to reduce the MPN disease burden.
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Affiliation(s)
- Vikas Bhuria
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Center for Health and Medical Prevention-ChaMP, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Conny K Baldauf
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Burkhart Schraven
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Center for Health and Medical Prevention-ChaMP, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Thomas Fischer
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Center for Health and Medical Prevention-ChaMP, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
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15
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Torres DG, Paes J, da Costa AG, Malheiro A, Silva GV, Mourão LPDS, Tarragô AM. JAK2 Variant Signaling: Genetic, Hematologic and Immune Implication in Chronic Myeloproliferative Neoplasms. Biomolecules 2022; 12:291. [PMID: 35204792 PMCID: PMC8961666 DOI: 10.3390/biom12020291] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/04/2022] [Accepted: 02/05/2022] [Indexed: 02/04/2023] Open
Abstract
The JAK2V617F variant constitutes a genetic alteration of higher frequency in BCR/ABL1 negative chronic myeloproliferative neoplasms, which is caused by a substitution of a G ˃ T at position 1849 and results in the substitution of valine with phenylalanine at codon 617 of the polypeptide chain. Clinical, morphological and molecular genetic features define the diagnosis criteria of polycythemia vera, essential thrombocythemia and primary myelofibrosis. Currently, JAK2V617F is associated with clonal hematopoiesis, genomic instability, dysregulations in hemostasis and immune response. JAK2V617F clones induce an inflammatory immune response and lead to a process of immunothrombosis. Recent research has shown great interest in trying to understand the mechanisms associated with JAK2V617F signaling and activation of cellular and molecular responses that progressively contribute to the development of inflammatory and vascular conditions in association with chronic myeloproliferative neoplasms. Thus, the aim of this review is to describe the main genetic, hematological and immunological findings that are linked to JAK2 variant signaling in chronic myeloproliferative neoplasms.
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Affiliation(s)
- Dania G. Torres
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil; (D.G.T.); (J.P.); (A.G.d.C.); (A.M.); (G.V.S.)
| | - Jhemerson Paes
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil; (D.G.T.); (J.P.); (A.G.d.C.); (A.M.); (G.V.S.)
| | - Allyson G. da Costa
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil; (D.G.T.); (J.P.); (A.G.d.C.); (A.M.); (G.V.S.)
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus 69067-005, AM, Brazil
| | - Adriana Malheiro
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil; (D.G.T.); (J.P.); (A.G.d.C.); (A.M.); (G.V.S.)
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus 69067-005, AM, Brazil
| | - George V. Silva
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil; (D.G.T.); (J.P.); (A.G.d.C.); (A.M.); (G.V.S.)
- Fundação Oswaldo Cruz–Instituto Leônidas e Maria Deane (Fiocruz), Manaus 69027-070, AM, Brazil
- Fundação Centro de Controle de Oncologia do Amazonas (FCECON), Manaus 69040-010, AM, Brazil
| | - Lucivana P. de Souza Mourão
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil; (D.G.T.); (J.P.); (A.G.d.C.); (A.M.); (G.V.S.)
| | - Andréa M. Tarragô
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69850-000, AM, Brazil; (D.G.T.); (J.P.); (A.G.d.C.); (A.M.); (G.V.S.)
- Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (FHEMOAM), Manaus 69050-001, AM, Brazil
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16
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Sobas M, Podolak-Dawidziak M, Lewandowski K, Bator M, Wróbel T. Primary Immune Thrombocytopenia and Essential Thrombocythemia: So Different and yet Somehow Similar-Cases Series and a Review of the Literature. Int J Mol Sci 2021; 22:10918. [PMID: 34681577 PMCID: PMC8539407 DOI: 10.3390/ijms222010918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/02/2021] [Accepted: 10/06/2021] [Indexed: 12/02/2022] Open
Abstract
This article collects several published cases in which immune thrombocytopenic purpura (ITP) is followed by essential thrombocythemia (ET) and vice versa. This surprising clinical condition is possible, but very rare and difficult to diagnose and manage. We have made an attempt to analyse the possible causes of the sequential appearance of ITP and ET taking into consideration the following: alteration of the thrombopoietin (TPO) receptor, the role of autoimmunity and inflammation, and cytokine modulation. A better understanding of these interactions may provide opportunities to determine predisposing factors and aid in finding new treatment modalities both for ITP and ET patients.
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Affiliation(s)
- Marta Sobas
- Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Pasteura 4, 50-367 Wroclaw, Poland; (M.P.-D.); (M.B.); (T.W.)
| | - Maria Podolak-Dawidziak
- Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Pasteura 4, 50-367 Wroclaw, Poland; (M.P.-D.); (M.B.); (T.W.)
| | - Krzysztof Lewandowski
- Hematology and Bone Marrow Transplantation Department, University of Medical Sciences, 60-569 Poznan, Poland;
| | - Michał Bator
- Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Pasteura 4, 50-367 Wroclaw, Poland; (M.P.-D.); (M.B.); (T.W.)
| | - Tomasz Wróbel
- Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Pasteura 4, 50-367 Wroclaw, Poland; (M.P.-D.); (M.B.); (T.W.)
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17
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Masselli E, Pozzi G, Carubbi C, Vitale M. The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome. Cells 2021; 10:cells10102597. [PMID: 34685575 PMCID: PMC8534117 DOI: 10.3390/cells10102597] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/06/2021] [Accepted: 09/24/2021] [Indexed: 12/14/2022] Open
Abstract
Myeloproliferative neoplasms are hematologic malignancies typified by a substantial heritable component. Germline variants may affect the risk of developing a MPN, as documented by GWAS studies on large patient cohorts. In addition, once the MPN occurred, inherited host genetic factors can be responsible for tuning the disease phenotypic presentation, outcome, and response to therapy. This review covered the polymorphisms that have been variably associated to MPNs, discussing them in the functional perspective of the biological pathways involved. Finally, we reviewed host genetic determinants of clonal hematopoiesis, a pre-malignant state that may anticipate overt hematologic neoplasms including MPNs.
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Affiliation(s)
- Elena Masselli
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, 43126 Parma, Italy; (E.M.); (G.P.)
- University Hospital of Parma, AOU-PR, 43126 Parma, Italy
| | - Giulia Pozzi
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, 43126 Parma, Italy; (E.M.); (G.P.)
| | - Cecilia Carubbi
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, 43126 Parma, Italy; (E.M.); (G.P.)
- Correspondence: (C.C.); (M.V.)
| | - Marco Vitale
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, 43126 Parma, Italy; (E.M.); (G.P.)
- University Hospital of Parma, AOU-PR, 43126 Parma, Italy
- Correspondence: (C.C.); (M.V.)
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18
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Hasselbalch HC, Skov V, Kjær L, Ellervik C, Poulsen A, Poulsen TD, Nielsen CH. COVID-19 as a mediator of interferon deficiency and hyperinflammation: Rationale for the use of JAK1/2 inhibitors in combination with interferon. Cytokine Growth Factor Rev 2021; 60:28-45. [PMID: 33992887 PMCID: PMC8045432 DOI: 10.1016/j.cytogfr.2021.03.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/26/2021] [Accepted: 03/27/2021] [Indexed: 02/08/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an interferon (IFN) deficiency state, which aggravates the type I interferon deficiency and slow IFN responses, which associate with e.g. aging and obesity. Additionally, SARS-CoV-2 may also elicit a cytokine storm, which accounts for disease progression and ultimately the urgent need of ventilator support. Based upon several reports, it has been argued that early treatment with IFN-alpha2 or IFN-beta, preferentially in the early disease stage, may prohibit disease progression. Similarly, preliminary studies have shown that JAK1/2 inhibitor treatment with ruxolitinib or baricitinib may decrease mortality by dampening the deadly cytokine storm, which - in addition to the virus itself - also contributes to multi-organ thrombosis and multi-organ failure. Herein, we describe the rationale for treatment with IFNs (alpha2 or beta) and ruxolitinib emphasizing the urgent need to explore these agents in the treatment of SARS-CoV-2 - both as monotherapies and in combination. In this context, we take advantage of several safety and efficacy studies in patients with the chronic myeloproliferative blood cancers (essential thrombocythemia, polycythemia vera and myelofibrosis) (MPNs), in whom IFN-alpha2 and ruxolitinib have been used successfully for the last 10 (ruxolitinib) to 30 years (IFN) as monotherapies and most recently in combination as well. In the context of these agents being highly immunomodulating (IFN boosting immune cells and JAK1/2 inhibitors being highly immunosuppressive and anti-inflammatory), we also discuss if statins and hydroxyurea, both agents possessing anti-inflammatory, antithrombotic and antiviral potentials, might be inexpensive agents to be repurposed in the treatment of SARS-CoV-2.
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Affiliation(s)
- H C Hasselbalch
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark.
| | - V Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - L Kjær
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - C Ellervik
- Department of Research, Production, Innovation, Region Zealand, Denmark; Department of Pathology, Harvard Medical School, Boston, MA, United States; Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA, United States
| | - A Poulsen
- Department of Anestesiology and Intensive Care Unit, Zealand University Hospital, Roskilde, Denmark
| | - T D Poulsen
- Department of Anestesiology and Intensive Care Unit, Zealand University Hospital, Roskilde, Denmark
| | - C H Nielsen
- Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis. Cancers (Basel) 2021; 13:cancers13112552. [PMID: 34067466 PMCID: PMC8196972 DOI: 10.3390/cancers13112552] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/15/2021] [Accepted: 05/17/2021] [Indexed: 01/11/2023] Open
Abstract
Simple Summary Among myeloproliferative neoplasms, primary myelofibrosis (PMF) is considered the paradigm of inflammation-related cancer development. Host genetic variants such as single nucleotide polymorphisms (SNPs) can affect cytokine/chemokine gene expression and may therefore have a role in a disease with a strong inflammatory component such as PMF. Here we demonstrate that the homozygosity for the rs1024611 SNP of the chemokine CCL2 represents a high-risk variant and a novel host genetic determinant of reduced survival in PMF, providing opportunities for CCL2 SNP genotyping as a potential novel strategy to risk-stratify patients. The rs1024611 genotype also influences CCL2 production in PMF cells, which are electively sensitive to CCL2 effects because of their unique expression of its receptor CCR2. Finally, ruxolitinib is capable of effectively down-regulating CCR2 expression, de-sensitizing PMF cells to the IL-1β-dependent pro-inflammatory stimulus. Abstract Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2—one of the most potent immunomodulatory chemokines—to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes; ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor); iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation; iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications.
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Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro. Blood Adv 2021; 4:3000-3010. [PMID: 32614965 DOI: 10.1182/bloodadvances.2019001292] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 05/26/2020] [Indexed: 02/02/2023] Open
Abstract
Acute myeloid leukemia (AML) is characterized by a high relapse rate and dismal long-term overall survival which is related to persistence of leukemia-initiating cells in their niche. Different animal models of myeloid malignancies reveal how neoplastic cells alter the structural and functional characteristics of the hematopoietic stem cell niche to reinforce malignancy. Understanding and disruption of the microenvironmental interactions with AML cells are a vital need. Malignant niches frequently go along with inflammatory responses, but their impact on cancerogenesis often remains unexplored. Here, we uncovered an aberrant production of inflammatory cytokines in untreated AML bone marrow that was proved to promote the proliferation of leukemia cells. This inflammatory response induced an activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in AML blasts as well as bone marrow stromal cells that also fostered leukemia proliferation. Inhibition of JAK/STAT signaling using the selective JAK1/2 inhibitor ruxolitinib resulted in significant antileukemic activity in AML in vitro which is mediated through both cell-autonomous and microenvironment-mediated mechanisms. However, in a xenograft transplantation model, monotherapy with ruxolitinib did not achieve substantial antileukemic activity, possibly suggesting a complementary function of JAK1/2 inhibition in AML.
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TET2 rs1548483 SNP Associating with Susceptibility to Molecularly Annotated Polycythemia Vera and Primary Myelofibrosis. J Pers Med 2020; 10:jpm10040259. [PMID: 33271790 PMCID: PMC7711989 DOI: 10.3390/jpm10040259] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 11/25/2020] [Accepted: 11/29/2020] [Indexed: 12/13/2022] Open
Abstract
Background: The complexity of myeloproliferative neoplasms (MPNs) cannot be characterized by acquired somatic mutations alone. Individual genetic background is thought to contribute to the development of MPNs. The aim of our study was to assess the association between the TET2 rs1548483 single nucleotide polymorphism (SNP) and the susceptibility to polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) or chronic myeloid leukemia (CML). Methods: We evaluated the TET2 rs1548483 SNP through real-time PCR in 1601 MPN patients out of which 431 with PV, 688 with TE, 233 with PMF, 249 with CML and 197 controls. We included only patients with a molecularly proven driver mutation, such as JAK2 V617F, CALR or BCR-ABL1. Results: Significant association between TET2 rs154843 variant allele and JAK2 V617F-positive PV and PMF (OR = 1.70; 95% CI: 1.01–2.91; p-value = 0.046, and OR = 2.04; 95% CI: 1.10–3.77; p-value = 0.024, respectively), and type 2 CALR-positive PMF (OR = 2.98; 95% CI: 1.12–7.93; p-value = 0.035) was noted. Conclusions: The TET2 rs1548483 SNP is associated with the susceptibility to molecularly annotated PV and PMF.
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Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR-ABL-Negative Myeloproliferative Neoplasm. Antioxidants (Basel) 2020; 9:antiox9111037. [PMID: 33114087 PMCID: PMC7690801 DOI: 10.3390/antiox9111037] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/06/2020] [Accepted: 10/21/2020] [Indexed: 12/11/2022] Open
Abstract
Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have recently been revealed to be related to chronic inflammation, oxidative stress, and the accumulation of reactive oxygen species. It has been proposed that MPNs represent a human inflammation model for tumor advancement, in which long-lasting inflammation serves as the driving element from early tumor stage (over polycythemia vera) to the later myelofibrotic cancer stage. It has been theorized that the starting event for acquired stem cell alteration may occur after a chronic inflammation stimulus with consequent myelopoietic drive, producing a genetic stem cell insult. When this occurs, the clone itself constantly produces inflammatory components in the bone marrow; these elements further cause clonal expansion. In BCR-ABL1-negative MPNs, the driver mutations include JAK 2, MPL, and CALR. Transcriptomic studies of hematopoietic stem cells from subjects with driver mutations have demonstrated the upregulation of inflammation-related genes capable of provoking the development of an inflammatory state. The possibility of acting on the inflammatory state as a therapeutic approach in MPNs appears promising, in which an intervention operating on the pathways that control the synthesis of cytokines and oxidative stress could be effective in reducing the possibility of leukemic progression and onset of complications.
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Masselli E, Pozzi G, Gobbi G, Merighi S, Gessi S, Vitale M, Carubbi C. Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants. Cells 2020. [PMID: 32967342 DOI: 10.3390/cells9092136.pmid:32967342;pmcid:pmc7564952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.
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Affiliation(s)
- Elena Masselli
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy
- University Hospital of Parma, AOU-PR, Via Gramsci 14, 43126 Parma, Italy
| | - Giulia Pozzi
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Giuliana Gobbi
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Stefania Merighi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Stefania Gessi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Marco Vitale
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy
- University Hospital of Parma, AOU-PR, Via Gramsci 14, 43126 Parma, Italy
| | - Cecilia Carubbi
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy
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Masselli E, Pozzi G, Gobbi G, Merighi S, Gessi S, Vitale M, Carubbi C. Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants. Cells 2020; 9:cells9092136. [PMID: 32967342 PMCID: PMC7564952 DOI: 10.3390/cells9092136] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/18/2020] [Accepted: 09/19/2020] [Indexed: 12/16/2022] Open
Abstract
Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.
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Affiliation(s)
- Elena Masselli
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy; (G.P.); (G.G.); (C.C.)
- University Hospital of Parma, AOU-PR, Via Gramsci 14, 43126 Parma, Italy
- Correspondence: (E.M.); (M.V.); Tel.: +39-052-190-6655 (E.M.); +39-052-103-3032 (M.V.)
| | - Giulia Pozzi
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy; (G.P.); (G.G.); (C.C.)
| | - Giuliana Gobbi
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy; (G.P.); (G.G.); (C.C.)
| | - Stefania Merighi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; (S.M.); (S.G.)
| | - Stefania Gessi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; (S.M.); (S.G.)
| | - Marco Vitale
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy; (G.P.); (G.G.); (C.C.)
- University Hospital of Parma, AOU-PR, Via Gramsci 14, 43126 Parma, Italy
- Correspondence: (E.M.); (M.V.); Tel.: +39-052-190-6655 (E.M.); +39-052-103-3032 (M.V.)
| | - Cecilia Carubbi
- Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy; (G.P.); (G.G.); (C.C.)
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Allain-Maillet S, Bosseboeuf A, Mennesson N, Bostoën M, Dufeu L, Choi EH, Cleyrat C, Mansier O, Lippert E, Le Bris Y, Gombert JM, Girodon F, Pettazzoni M, Bigot-Corbel E, Hermouet S. Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms. Cancers (Basel) 2020; 12:cancers12092446. [PMID: 32872203 PMCID: PMC7564615 DOI: 10.3390/cancers12092446] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 08/24/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Inflammation plays a major role in myeloproliferative neoplasms (MPNs) as regulator of malignant cell growth and mediator of clinical symptoms. Yet chronic inflammation may also be an early event that facilitates the development of MPNs. Here we analysed 42 inflammatory cytokines and report that in patients as well as in UT-7 cell lines, interleukin-1β and interferon-induced protein 10 (IP-10) were the main inflammatory molecules found to be induced by JAK2V617F, the most frequent driving mutation in MPNs. All other inflammatory cytokines were not linked to JAK2V617F, which implies that inflammation likely precedes MPN development at least in subsets of MPN patients. Consistently, a possible cause of early, chronic inflammation may be auto-immunity against glucolipids: we report that 20% of MPN patients presented with anti-glucosylsphingoside auto-antibodies. Since existing treatments can reduce glucosylsphingoside, this lysosphingolipid could become a new therapeutic target for subsets of MPN patients, in addition to JAK2V617F and inflammation. Abstract Inflammatory cytokines play a major role in myeloproliferative neoplasms (MPNs) as regulators of the MPN clone and as mediators of clinical symptoms and complications. Firstly, we investigated the effect of JAK2V617F on 42 molecules linked to inflammation. For JAK2V617F-mutated patients, the JAK2V617F allele burden (%JAK2V617F) correlated with the levels of IL-1β, IL-1Rα, IP-10 and leptin in polycythemia vera (PV), and with IL-33 in ET; for all other molecules, no correlation was found. Cytokine production was also studied in the human megakaryocytic cell line UT-7. Wild-type UT-7 cells secreted 27/42 cytokines measured. UT-7 clones expressing 50% or 75% JAK2V617F were generated, in which the production of IL-1β, IP-10 and RANTES was increased; other cytokines were not affected. Secondly, we searched for causes of chronic inflammation in MPNs other than driver mutations. Since antigen-driven selection is increasingly implicated in the pathogenesis of blood malignancies, we investigated whether proinflammatory glucosylsphingosine (GlcSph) may play a role in MPNs. We report that 20% (15/75) of MPN patients presented with anti-GlcSph IgGs, distinguished by elevated levels of 11 cytokines. In summary, only IL-1β and IP-10 were linked to JAK2V617F both in patients and in UT-7 cells; other inflammation-linked cytokines in excess in MPNs were not. For subsets of MPN patients, a possible cause of inflammation may be auto-immunity against glucolipids.
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Affiliation(s)
- Sophie Allain-Maillet
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1232, CRCINA, University of Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France; (S.A.-M.); (A.B.); (N.M.); (M.B.); (L.D.); (Y.L.B.); (E.B.-C.)
| | - Adrien Bosseboeuf
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1232, CRCINA, University of Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France; (S.A.-M.); (A.B.); (N.M.); (M.B.); (L.D.); (Y.L.B.); (E.B.-C.)
| | - Nicolas Mennesson
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1232, CRCINA, University of Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France; (S.A.-M.); (A.B.); (N.M.); (M.B.); (L.D.); (Y.L.B.); (E.B.-C.)
| | - Mégane Bostoën
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1232, CRCINA, University of Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France; (S.A.-M.); (A.B.); (N.M.); (M.B.); (L.D.); (Y.L.B.); (E.B.-C.)
| | - Laura Dufeu
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1232, CRCINA, University of Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France; (S.A.-M.); (A.B.); (N.M.); (M.B.); (L.D.); (Y.L.B.); (E.B.-C.)
| | - Eun Ho Choi
- Department of Pathology & Comprehensive Cancer Center, University of New Mexico (NM) Health Sciences Center, Albuquerque, NM 87102 USA; (E.H.C.); (C.C.)
| | - Cédric Cleyrat
- Department of Pathology & Comprehensive Cancer Center, University of New Mexico (NM) Health Sciences Center, Albuquerque, NM 87102 USA; (E.H.C.); (C.C.)
| | - Olivier Mansier
- Laboratoire d’Hématologie, CHU de Bordeaux, 33600 Pessac, France;
- INSERM U1034, Université de Bordeaux, UFR Sciences de la Vie et de la Santé, 33000 Bordeaux, France
| | - Eric Lippert
- Laboratoire d’Hématologie, CHU de Brest, 29200 Brest, France;
- INSERM, Etablissement Français du Sang (EFS), UMR 1078, GGB, Université de Brest, 29200 Brest, France
| | - Yannick Le Bris
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1232, CRCINA, University of Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France; (S.A.-M.); (A.B.); (N.M.); (M.B.); (L.D.); (Y.L.B.); (E.B.-C.)
- Laboratoire d’Hématologie, CHU de Nantes, 44093 Nantes, France
| | | | - François Girodon
- Laboratoire d’Hématologie, CHU Dijon, 21034 Dijon, France;
- INSERM, UMR 1231, University of Bourgogne Franche-Comté, 21078 Dijon, France
| | - Magali Pettazzoni
- LBMMS, Service de Biochimie et Biologie Moléculaire Grand Est, UF des Maladies Héréditaires du Métabolisme, Hospices Civils de Lyon, 69677 Bron CEDEX, France;
| | - Edith Bigot-Corbel
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1232, CRCINA, University of Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France; (S.A.-M.); (A.B.); (N.M.); (M.B.); (L.D.); (Y.L.B.); (E.B.-C.)
- Laboratoire de Biochimie, CHU de Nantes, 44093 Nantes, France
| | - Sylvie Hermouet
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1232, CRCINA, University of Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France; (S.A.-M.); (A.B.); (N.M.); (M.B.); (L.D.); (Y.L.B.); (E.B.-C.)
- Laboratoire d’Hématologie, CHU de Nantes, 44093 Nantes, France
- Correspondence: ; Tel.: +33-228080355
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Hasselbalch HC. Cytokine Profiling as a Novel Complementary Tool to Predict Prognosis in MPNs? Hemasphere 2020; 4:e407. [PMID: 32647805 PMCID: PMC7306306 DOI: 10.1097/hs9.0000000000000407] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 04/28/2020] [Indexed: 02/03/2023] Open
Affiliation(s)
- Hans C Hasselbalch
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
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27
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Defective negative regulation of Toll-like receptor signaling leads to excessive TNF-α in myeloproliferative neoplasm. Blood Adv 2020; 3:122-131. [PMID: 30647074 PMCID: PMC6341195 DOI: 10.1182/bloodadvances.2018026450] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 12/12/2018] [Indexed: 12/12/2022] Open
Abstract
Patients with myeloproliferative neoplasms (MPN) have high levels of inflammatory cytokines, some of which drive many of the debilitating constitutional symptoms associated with the disease and may also promote expansion of the neoplastic clone. We report here that monocytes from patients with MPN have defective negative regulation of Toll-like receptor (TLR) signaling that leads to unrestrained production of the inflammatory cytokine tumor necrosis factor α (TNF-α) after TLR activation. Specifically, monocytes of patients with MPN are insensitive to the anti-inflammatory cytokine interleukin 10 (IL-10) that negatively regulates TLR-induced TNF-α production. This inability to respond to IL-10 is a not a direct consequence of JAK2 V617F , as the phenotype of persistent TNF-α production is a feature of JAK2 V617F and wild-type monocytes alike from JAK2 V617F -positive patients. Moreover, persistent TNF-α production was also discovered in the unaffected identical twin of a patient with MPN, suggesting it could be an intrinsic feature of those predisposed to acquire MPN. This work implicates sustained TLR signaling as not only a contributor to the chronic inflammatory state of MPN patients but also a potential predisposition to acquire MPN.
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Vannucchi AM, Guglielmelli P. The JAK2 46/1 (GGCC) MPN-predisposing haplotype: A risky haplotype, after all. Am J Hematol 2019; 94:283-285. [PMID: 30499143 DOI: 10.1002/ajh.25367] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 11/26/2018] [Indexed: 01/12/2023]
Affiliation(s)
- Alessandro M. Vannucchi
- CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica; Università degli Studi Firenze, and DENOTHE Excellence Center; Firenze Italy
| | - Paola Guglielmelli
- CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica; Università degli Studi Firenze, and DENOTHE Excellence Center; Firenze Italy
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Tefferi A, Lasho TL, Mudireddy M, Finke CM, Hanson CA, Ketterling RP, Gangat N, Pardanani A. The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly-annotated patients with primary myelofibrosis. Am J Hematol 2019; 94:299-305. [PMID: 30516848 DOI: 10.1002/ajh.25349] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 01/07/2023]
Abstract
JAK2 mutations in myeloproliferative neoplasms (MPNs) are associated with the germline GGCC (46/1) haplotype. In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype. In the current study, we have increased the number of informative cases from 130 to 414 (median age 63 years; 63% males), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL, and 6%/10%/14% triple-negative (P = .02). In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9), most pronounced in JAK2 (P <.001), as opposed to CALR/MPL mutated (P = .48) or triple-negative cases (P = .27). Multivariable analysis that included karyotype, driver mutational status and high-molecular risk mutations confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (P = .02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the genetically-inspired GIPSS risk model (P = .04), but not in the context of the integrated genetics-clinical MIPSS70+ version 2.0 model (P = .4). Leukemia-free survival was not affected by the 46/1 haplotype (P = .6). The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in JAK2-mutated PMF.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology; Mayo Clinic; Rochester Minnesota
| | - Terra L. Lasho
- Division of Hematology; Mayo Clinic; Rochester Minnesota
| | | | | | | | - Rhett P. Ketterling
- Divisions of Laboratory Genetics and Genomics, Departments of Internal Medicine and Laboratory Medicine; Mayo Clinic; Rochester Minnesota
| | - Naseema Gangat
- Division of Hematology; Mayo Clinic; Rochester Minnesota
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Bjørn ME, Brimnes MK, Gudbrandsdottir S, Andersen CL, Poulsen HE, Henriksen T, Hasselbalch HC, Nielsen CH. Ruxolitinib treatment reduces monocytic superoxide radical formation without affecting hydrogen peroxide formation or systemic oxidative nucleoside damage in myelofibrosis. Leuk Lymphoma 2019; 60:2549-2557. [PMID: 30785365 DOI: 10.1080/10428194.2019.1579323] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The role of excess reactive oxygen species (ROS) with consequent DNA/RNA damage is now recognized as a hallmark of cancer. In JAK2V617F mutated myeloproliferative neoplasms, ROS have been suggested to be important factors in disease initiation and progression. Ruxolitinib is the most widely used drug for myelofibrosis, because it improves symptom-score. However, both the anti-clonal potential and improvement in overall survival are limited. We investigated the impact of ruxolitinib on formation of superoxide radical and hydrogen peroxide by monocytes in sequentially acquired blood samples from patients with myelofibrosis. We also investigated the impact on RNA and DNA damage by measuring urinary excretion of 8-oxo-Guo and 8-oxo-d-Guo. The formation of superoxide by monocytes was reduced significantly during ruxolitinib therapy, but no impact on the formation of hydrogen peroxide by monocytes or the systemic amount of oxidatively damaged RNA or DNA could be demonstrated. We conclude that ruxolitinib holds little anti-oxidative potential.
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Affiliation(s)
- Mads Emil Bjørn
- Department of Hematology, Region Zealand University, Roskilde Hospital , Roskilde , Denmark.,Institute for Inflammation Research (IIR), Center for Rheumatology and Spine Diseases, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark
| | - Marie Klinge Brimnes
- Institute for Inflammation Research (IIR), Center for Rheumatology and Spine Diseases, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark
| | - Sif Gudbrandsdottir
- Institute for Inflammation Research (IIR), Center for Rheumatology and Spine Diseases, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.,Department of Hematology, Herlev Hospital , Herlev , Denmark
| | | | - Henrik Enghusen Poulsen
- Laboratory of Clinical Pharmacology Q7642, University of Copenhagen, Rigshospitalet , Copenhagen , Denmark.,Department of Clinical Pharmacology, Bispebjerg Hospital, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Trine Henriksen
- Laboratory of Clinical Pharmacology Q7642, University of Copenhagen, Rigshospitalet , Copenhagen , Denmark
| | - Hans Carl Hasselbalch
- Department of Hematology, Region Zealand University, Roskilde Hospital , Roskilde , Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Claus Henrik Nielsen
- Institute for Inflammation Research (IIR), Center for Rheumatology and Spine Diseases, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
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Darcy H, Simpson K, Gajanayake I, Seth M, McGrotty Y, Szladovits B, Glanemann B. Feline primary erythrocytosis: a multicentre case series of 18 cats. J Feline Med Surg 2018; 20:1192-1198. [PMID: 29364032 PMCID: PMC11104208 DOI: 10.1177/1098612x17750333] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
CASE SERIES SUMMARY A retrospective multicentre case series of feline primary erythrocytosis (PE) was evaluated. The aim was to gain better understanding of disease presentation and progression to guide management and prognostication. Case records were assessed for evidence of increased packed cell volume (PCV; >48%), sufficient investigation to rule out relative and secondary erythrocytosis, and follow-up data for at least 12 months or until death. Eighteen cats were included in the case series. No significant trends in signalment were noted. Seizures and mentation changes were the most common presenting signs (both n = 10). Median PCV was 70% (median total protein concentration of 76 g/l) with no other consistent haematological changes. Sixteen cats survived to discharge. Phlebotomy was performed initially in 15/16 surviving animals and performed after discharge in 10/16. Hydroxyurea was the most common adjunctive therapy, used in 10/16 cats. Of the 16 patients surviving to discharge, 14 patients were still alive at the conclusion of the study (survival time >17 months post-discharge), with the two non-survivors having lived for 5 years or more after diagnosis. PCV, when stabilised, did not correlate with resolution of clinical signs. RELEVANCE AND NOVEL INFORMATION In contrast to perceptions, feline PE was generally well managed via a combination of phlebotomy and medical therapy, with evidence of prolonged survival times. The use of hydroxyurea enabled cessation or repeat phlebotomies.
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Affiliation(s)
- Hannah Darcy
- Queen Mother Hospital for Animals, Department of Clinical Science and Services, Royal Veterinary College, North Mymms, Hertfordshire, UK
| | - Katherine Simpson
- Goddard Veterinary Group, Mandeville Veterinary Hospital, Northolt, UK
| | - Isuru Gajanayake
- Willows Veterinary Centre and Referral Service, Solihull, West Midlands, UK
| | - Mayank Seth
- Centre for Small Animal Studies, Animal Health Trust, Newmarket, Suffolk, UK
| | | | - Balazs Szladovits
- Diagnostic Laboratory Services, Department of Pathobiology and Population Sciences, Royal Veterinary College, North Mymms, Hertfordshire, UK
| | - Barbara Glanemann
- Queen Mother Hospital for Animals, Department of Clinical Science and Services, Royal Veterinary College, North Mymms, Hertfordshire, UK
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Anelli L, Zagaria A, Specchia G, Albano F. The JAK2 GGCC (46/1) Haplotype in Myeloproliferative Neoplasms: Causal or Random? Int J Mol Sci 2018; 19:ijms19041152. [PMID: 29641446 PMCID: PMC5979434 DOI: 10.3390/ijms19041152] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/05/2018] [Accepted: 04/09/2018] [Indexed: 12/11/2022] Open
Abstract
The germline JAK2 haplotype known as “GGCC or 46/1 haplotype” (haplotypeGGCC_46/1) consists of a combination of single nucleotide polymorphisms (SNPs) mapping in a region of about 250 kb, extending from the JAK2 intron 10 to the Insulin-like 4 (INLS4) gene. Four main SNPs (rs3780367, rs10974944, rs12343867, and rs1159782) generating a “GGCC” combination are more frequently indicated to represent the JAK2 haplotype. These SNPs are inherited together and are frequently associated with the onset of myeloproliferative neoplasms (MPN) positive for both JAK2 V617 and exon 12 mutations. The association between the JAK2 haplotypeGGCC_46/1 and mutations in other genes, such as thrombopoietin receptor (MPL) and calreticulin (CALR), or the association with triple negative MPN, is still controversial. This review provides an overview of the frequency and the role of the JAK2 haplotypeGGCC_46/1 in the pathogenesis of different myeloid neoplasms and describes the hypothetical mechanisms at the basis of the association with JAK2 gene mutations. Moreover, possible clinical implications are discussed, as different papers reported contrasting data about the correlation between the JAK2 haplotypeGGCC_46/1 and blood cell count, survival, or disease progression.
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Affiliation(s)
- Luisa Anelli
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
| | - Antonella Zagaria
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
| | - Giorgina Specchia
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
| | - Francesco Albano
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
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33
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Craver BM, El Alaoui K, Scherber RM, Fleischman AG. The Critical Role of Inflammation in the Pathogenesis and Progression of Myeloid Malignancies. Cancers (Basel) 2018; 10:cancers10040104. [PMID: 29614027 PMCID: PMC5923359 DOI: 10.3390/cancers10040104] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 03/23/2018] [Accepted: 04/02/2018] [Indexed: 12/15/2022] Open
Abstract
Hematopoietic stem cells (HSCs) maintain an organism's immune system for a lifetime, and derangements in HSC proliferation and differentiation result in hematologic malignancies. Chronic inflammation plays a contributory if not causal role in HSC dysfunction. Inflammation induces HSC exhaustion, which promotes the emergence of mutant clones that may be resistant to an inflammatory microenvironment; this likely promotes the onset of a myeloid hematologic malignancy. Inflammatory cytokines are characteristically high in patients with myeloid malignancies and are linked to disease initiation, symptom burden, disease progression, and worsened prognostic survival. This review will cover our current understanding of the role of inflammation in the initiation, progression, and complications of myeloid hematologic malignancies, drawing from clinical studies as well as murine models. We will also highlight inflammation as a therapeutic target in hematologic malignancies.
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Affiliation(s)
- Brianna M Craver
- Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA.
| | - Kenza El Alaoui
- Department of Internal Medicine, Université Libre de Bruxelles, 1050 Brussels, Belgium.
- Department of Medicine, University of California Irvine, Irvine, CA 92697, USA.
| | - Robyn M Scherber
- Department of Hematology and Oncology, Mays MD Anderson Cancer Center, University of Texas San Antonio, San Antonio, TX 78249, USA.
| | - Angela G Fleischman
- Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA.
- Department of Medicine, University of California Irvine, Irvine, CA 92697, USA.
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34
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Karantanos T, Moliterno AR. The roles of JAK2 in DNA damage and repair in the myeloproliferative neoplasms: Opportunities for targeted therapy. Blood Rev 2018; 32:426-432. [PMID: 29627078 DOI: 10.1016/j.blre.2018.03.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/03/2018] [Accepted: 03/27/2018] [Indexed: 02/09/2023]
Abstract
The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN. On the other hand, JAK2 signaling normally induces DDR through activation of repair mediators such as Chk1, RAD51 and RECQL5. These opposing effects on DNA integrity in the setting of JAK2V617F have significant clinical implications and have led to the introduction of novel combinational therapies for these diseases. The inhibition of MDM2 with Nutlin-3 improves the efficacy of IFN-α via decreased p53 degradation, the combination of hydroxyurea with Ruxolitinib, and their combination with PARP inhibitors have significant anti-tumor effects. A better understanding of the implication of JAK2 in the development and repair of DNA damage can improve our understanding of the biology of these neoplasms, meliorate the risk stratification of our patients and enrich our therapeutic armamentarium.
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Affiliation(s)
| | - Alison R Moliterno
- Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, USA.
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35
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Andersen M, Sajid Z, Pedersen RK, Gudmand-Hoeyer J, Ellervik C, Skov V, Kjær L, Pallisgaard N, Kruse TA, Thomassen M, Troelsen J, Hasselbalch HC, Ottesen JT. Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development. PLoS One 2017; 12:e0183620. [PMID: 28859112 PMCID: PMC5578482 DOI: 10.1371/journal.pone.0183620] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/08/2017] [Indexed: 12/15/2022] Open
Abstract
The chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms which ultimately may transform to acute myelogenous leukemia. Most recently, chronic inflammation has been described as an important factor for the development and progression of MPNs in the biological continuum from early cancer stage to the advanced myelofibrosis stage, the MPNs being described as "A Human Inflammation Model for Cancer Development". This novel concept has been built upon clinical, experimental, genomic, immunological and not least epidemiological studies. Only a few studies have described the development of MPNs by mathematical models, and none have addressed the role of inflammation for clonal evolution and disease progression. Herein, we aim at using mathematical modelling to substantiate the concept of chronic inflammation as an important trigger and driver of MPNs.The basics of the model describe the proliferation from stem cells to mature cells including mutations of healthy stem cells to become malignant stem cells. We include a simple inflammatory coupling coping with cell death and affecting the basic model beneath. First, we describe the system without feedbacks or regulatory interactions. Next, we introduce inflammatory feedback into the system. Finally, we include other feedbacks and regulatory interactions forming the inflammatory-MPN model. Using mathematical modeling, we add further proof to the concept that chronic inflammation may be both a trigger of clonal evolution and an important driving force for MPN disease progression. Our findings support intervention at the earliest stage of cancer development to target the malignant clone and dampen concomitant inflammation.
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Affiliation(s)
- Morten Andersen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Zamra Sajid
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Rasmus K. Pedersen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | | | - Christina Ellervik
- Department of Laboratory Medicine at Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Vibe Skov
- Department of Hematology, Zealand University Hospital, University of Copenhagen, Roskilde, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University Hospital, University of Copenhagen, Roskilde, Denmark
| | - Niels Pallisgaard
- Department of Pathology, Zealand University Hospital, University of Copenhagen, Roskilde, Denmark
| | - Torben A. Kruse
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Jesper Troelsen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Hans Carl Hasselbalch
- Department of Hematology, Zealand University Hospital, University of Copenhagen, Roskilde, Denmark
| | - Johnny T. Ottesen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
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36
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Bjørn ME, Hasselbalch HC. Minimal residual disease or cure in MPNs? Rationales and perspectives on combination therapy with interferon-alpha2 and ruxolitinib. Expert Rev Hematol 2017; 10:393-404. [DOI: 10.1080/17474086.2017.1284583] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Mads Emil Bjørn
- Department of Hematology, Region Zealand University Hospital, Roskilde, Denmark
- Institute for Inflammation Research, Center for Reumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
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37
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Skov V, Riley CH, Thomassen M, Kjær L, Stauffer Larsen T, Bjerrum OW, Kruse TA, Hasselbalch HC. The impact of interferon-alpha2 on HLA genes in patients with polycythemia vera and related neoplasms. Leuk Lymphoma 2016; 58:1914-1921. [PMID: 27911124 DOI: 10.1080/10428194.2016.1262032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gene expression profiling in Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have unraveled significant deregulation of several immune and inflammation genes of potential importance for clonal evolution. Other mechanisms might be downregulation of major histocompatibility class I and II genes used by tumor cells to escape antitumor T-cell-mediated immune responses. Several genes encoding human leukocyte antigen (HLA) class I and II molecules have been shown to be significantly downregulated. Upregulation of HLA genes is considered one of the mechanisms of action of interferon (IFN)-alpha2, but regulation of these genes during IFN-alpha2 treatment in MPNs has never been studied. Our findings show a significant upregulation of several HLA genes of importance for tumor immune surveillance by IFN-alpha2 treatment in MPNs. This mechanism might enhance the cytotoxic potential of immune cells against MPNs and explain the induction of minimal residual disease by IFN-alpha2 treatment in these patients.
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Affiliation(s)
- Vibe Skov
- a Department of Hematology , Zealand University Hospital , Roskilde , Denmark
| | - Caroline Hasselbalch Riley
- a Department of Hematology , Zealand University Hospital , Roskilde , Denmark.,b Center for Cancer Immune Therapy, Department of Hematology , Herlev Hospital, University of Copenhagen , Copenhagen , Denmark
| | - Mads Thomassen
- c Department of Clinical Genetics , Odense University Hospital , Odense , Denmark
| | - Lasse Kjær
- a Department of Hematology , Zealand University Hospital , Roskilde , Denmark
| | | | - Ole Weis Bjerrum
- e Department of Hematology L , Rigshospitalet, University of Copenhagen , Copenhagen , Denmark
| | - Torben A Kruse
- c Department of Clinical Genetics , Odense University Hospital , Odense , Denmark
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38
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Skov V, Burton M, Thomassen M, Stauffer Larsen T, Riley CH, Brinch Madelung A, Kjær L, Bondo H, Stamp I, Ehinger M, Dahl-Sørensen R, Brochmann N, Nielsen K, Thiele J, Jensen MK, Weis Bjerrum O, Kruse TA, Hasselbalch HC. A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis. PLoS One 2016; 11:e0161570. [PMID: 27579896 PMCID: PMC5007012 DOI: 10.1371/journal.pone.0161570] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 08/08/2016] [Indexed: 01/01/2023] Open
Abstract
Recent studies have shown that a large proportion of patients classified as essential thrombocythemia (ET) actually have early primary prefibrotic myelofibrosis (prePMF), which implies an inferior prognosis as compared to patients being diagnosed with so-called genuine or true ET. According to the World Health Organization (WHO) 2008 classification, bone marrow histology is a major component in the distinction between these disease entities. However, the differential diagnosis between them may be challenging and several studies have not been able to distinguish between them. Most lately, it has been argued that simple blood tests, including the leukocyte count and plasma lactate dehydrogenase (LDH) may be useful tools to separate genuine ET from prePMF, the latter disease entity more often being featured by anemia, leukocytosis and elevated LDH. Whole blood gene expression profiling was performed in 17 and 9 patients diagnosed with ET and PMF, respectively. Using elevated LDH obtained at the time of diagnosis as a marker of prePMF, a 7-gene signature was identified which correctly predicted the prePMF group with a sensitivity of 100% and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, and MMP8, which are genes known to be involved in inflammation, cell adhesion, differentiation and proliferation. Evaluation of bone marrow biopsies and the 7-gene signature showed a concordance rate of 71%, 79%, 62%, and 38%. Our 7-gene signature may be a useful tool to differentiate between genuine ET and prePMF but needs to be validated in a larger cohort of "ET" patients.
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Affiliation(s)
- Vibe Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Mark Burton
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | | | - Caroline H. Riley
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | | | - Lasse Kjær
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Henrik Bondo
- Department of Pathology, Naestved Hospital, Naestved, Denmark
| | - Inger Stamp
- Department of Pathology, Naestved Hospital, Naestved, Denmark
| | - Mats Ehinger
- Department of Pathology, Lund University Hospital, Lund, Sweden
| | | | - Nana Brochmann
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Karsten Nielsen
- Department of Pathology, University of Aarhus, Aarhus, Denmark
| | - Jürgen Thiele
- Institute of Pathology, University of Cologne, Köln, Germany
| | - Morten K. Jensen
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Ole Weis Bjerrum
- Department of Hematology L, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Torben A. Kruse
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
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Balassa K, Krahling T, Remenyi P, Batai A, Bors A, Kiss KP, Torbagyi E, Gopcsa L, Lengyel L, Barta A, Varga G, Tordai A, Masszi T, Andrikovics H. Recipient and donor JAK2 46/1 haplotypes are associated with acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma 2016; 58:391-398. [PMID: 27389386 DOI: 10.1080/10428194.2016.1198956] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Several genetic polymorphisms have been implicated to affect the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The role of cytokines in acute graft-versus-host disease (aGvHD) is well established and many of the involved cytokines signal through the Janus kinase (JAK) pathways. In this study, we assessed the association of recipient and donor JAK2 46/1 haplotypes and allo-HSCT outcome in a cohort of 124 acute myeloid leukemia patients. Both, recipient and donor 46/1 haplotypes significantly affected aGvHD grades II-IV development (p = 0.006 and p = 0.031, respectively), furthermore the influence of the haplotypes seemed to be additive. In multivariate analyses the recipient haplotype remained independently related (p = 0.012) to aGvHD, while the donor not (p = 0.08). We observed significantly less relapses among haplotype carriers (p = 0.004), but overall survival did not differ (p = 0.732). Our findings suggest that recipient and donor JAK2 46/1 haplotypes might be involved in the regulation of aGvHD.
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Affiliation(s)
- Katalin Balassa
- a School of PhD Studies , Semmelweis University , Budapest , Hungary.,b Laboratory of Molecular Diagnostics , Hungarian National Blood Transfusion Service , Budapest , Hungary
| | - Tunde Krahling
- a School of PhD Studies , Semmelweis University , Budapest , Hungary.,b Laboratory of Molecular Diagnostics , Hungarian National Blood Transfusion Service , Budapest , Hungary
| | - Peter Remenyi
- c Department of Hematology and Stem Cell Transplantation , St. Istvan and St. Laszlo Hospital , Budapest , Hungary
| | - Arpad Batai
- c Department of Hematology and Stem Cell Transplantation , St. Istvan and St. Laszlo Hospital , Budapest , Hungary
| | - Andras Bors
- b Laboratory of Molecular Diagnostics , Hungarian National Blood Transfusion Service , Budapest , Hungary
| | - Katalin Piroska Kiss
- b Laboratory of Molecular Diagnostics , Hungarian National Blood Transfusion Service , Budapest , Hungary
| | - Eva Torbagyi
- c Department of Hematology and Stem Cell Transplantation , St. Istvan and St. Laszlo Hospital , Budapest , Hungary
| | - Laszlo Gopcsa
- c Department of Hematology and Stem Cell Transplantation , St. Istvan and St. Laszlo Hospital , Budapest , Hungary
| | - Lilla Lengyel
- c Department of Hematology and Stem Cell Transplantation , St. Istvan and St. Laszlo Hospital , Budapest , Hungary
| | - Aniko Barta
- c Department of Hematology and Stem Cell Transplantation , St. Istvan and St. Laszlo Hospital , Budapest , Hungary
| | - Gergely Varga
- d 3rd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Attila Tordai
- b Laboratory of Molecular Diagnostics , Hungarian National Blood Transfusion Service , Budapest , Hungary.,e Department of Pathophysiology , Semmelweis University , Budapest , Hungary
| | - Tamas Masszi
- c Department of Hematology and Stem Cell Transplantation , St. Istvan and St. Laszlo Hospital , Budapest , Hungary.,d 3rd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Hajnalka Andrikovics
- b Laboratory of Molecular Diagnostics , Hungarian National Blood Transfusion Service , Budapest , Hungary
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40
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Hasselbalch HC, Bjørn ME. MPNs as Inflammatory Diseases: The Evidence, Consequences, and Perspectives. Mediators Inflamm 2015; 2015:102476. [PMID: 26604428 PMCID: PMC4641200 DOI: 10.1155/2015/102476] [Citation(s) in RCA: 155] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 09/17/2015] [Indexed: 12/30/2022] Open
Abstract
In recent years the evidence is increasing that chronic inflammation may be an important driving force for clonal evolution and disease progression in the Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Abnormal expression and activity of a number of proinflammatory cytokines are associated with MPNs, in particular MF, in which immune dysregulation is pronounced as evidenced by dysregulation of several immune and inflammation genes. In addition, chronic inflammation has been suggested to contribute to the development of premature atherosclerosis and may drive the development of other cancers in MPNs, both nonhematologic and hematologic. The MPN population has a substantial inflammation-mediated comorbidity burden. This review describes the evidence for considering the MPNs as inflammatory diseases, A Human Inflammation Model of Cancer Development, and the role of cytokines in disease initiation and progression. The consequences of this model are discussed, including the increased risk of second cancers and other inflammation-mediated diseases, emphasizing the urgent need for rethinking our therapeutic approach. Early intervention with interferon-alpha2, which as monotherapy has been shown to be able to induce minimal residual disease, in combination with potent anti-inflammatory agents such as JAK-inhibitors is foreseen as the most promising new treatment modality in the years to come.
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Affiliation(s)
- Hans Carl Hasselbalch
- Department of Hematology, Roskilde Hospital, University of Copenhagen, Køgevej 7-13, 4000 Roskilde, Denmark
| | - Mads Emil Bjørn
- Department of Hematology, Roskilde Hospital, University of Copenhagen, Køgevej 7-13, 4000 Roskilde, Denmark
- Institute for Inflammation Research, Department of Rheumatology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark
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41
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Hermouet S, Bigot-Corbel E, Gardie B. Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation. Mediators Inflamm 2015; 2015:145293. [PMID: 26538820 PMCID: PMC4619950 DOI: 10.1155/2015/145293] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 08/19/2015] [Indexed: 12/18/2022] Open
Abstract
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in the JAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients with JAK2-mutated MPNs may not be the consequence of JAK2 mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation.
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Affiliation(s)
- Sylvie Hermouet
- Inserm UMR 892, CNRS UMR 6299, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche en Santé, Université de Nantes, 44007 Nantes, France
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Nantes, 44093 Nantes Cedex, France
| | - Edith Bigot-Corbel
- Inserm UMR 892, CNRS UMR 6299, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche en Santé, Université de Nantes, 44007 Nantes, France
- Laboratoire de Biochimie, Centre Hospitalier Universitaire de Nantes, 44093 Nantes Cedex, France
| | - Betty Gardie
- Inserm UMR 892, CNRS UMR 6299, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche en Santé, Université de Nantes, 44007 Nantes, France
- Ecole Pratique des Hautes Etudes, Laboratoire de Génétique Oncologique, 44007 Nantes, France
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Hasselbalch HC. Smoking as a contributing factor for development of polycythemia vera and related neoplasms. Leuk Res 2015; 39:S0145-2126(15)30373-8. [PMID: 26463040 DOI: 10.1016/j.leukres.2015.09.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 08/29/2015] [Accepted: 09/04/2015] [Indexed: 12/17/2022]
Abstract
Smoking may be associated with accelerated erythropoiesis, leukocytosis and thrombocytosis, which are also hallmarks in patients with polycythemia vera, essential thrombocythemia and early stages of myelofibrosis (MPNs). The JAK-STAT and NF-κB signaling pathways are activated in both smokers and in patients with MPNs. Additionally, both share elevated levels of several proinflammatory cytokines, in vivo activation of leukocytes and platelets, endothelial dysfunction and increased systemic oxidative stress. Based upon experimental, epidemiological and clinical data it is herein argued and discussed, if smoking may be involved in MPN pathogenesis, considering most recent studies and reviews which are supportive of the concept that chronic inflammation with NF-κB activation and oxidative stress may have a major role - both as triggers but also as the driving force for clonal expansion in MPNs.
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Affiliation(s)
- Hans Carl Hasselbalch
- Department of Hematology, Roskilde Hospital, University of Copenhagen, Koegevej 7-13, 4000 Roskilde, Denmark.
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Soler G, Bernal-Vicente A, Antón AI, Torregrosa JM, Caparrós-Pérez E, Sánchez-Serrano I, Martínez-Pérez A, Sánchez-Vega B, Vicente V, Ferrer-Marin F. The JAK2 46/1 haplotype does not predispose to CALR-mutated myeloproliferative neoplasms. Ann Hematol 2014; 94:789-94. [DOI: 10.1007/s00277-014-2266-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 11/23/2014] [Indexed: 10/24/2022]
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Hasselbalch HC, Thomassen M, Hasselbalch Riley C, Kjær L, Stauffer Larsen T, Jensen MK, Bjerrum OW, Kruse TA, Skov V. Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms. Potential implications of downregulation of Nrf2 for genomic instability and disease progression. PLoS One 2014; 9:e112786. [PMID: 25397683 PMCID: PMC4232509 DOI: 10.1371/journal.pone.0112786] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 10/15/2014] [Indexed: 01/16/2023] Open
Abstract
The Philadelphia-negative chronic myeloproliferative neoplasms - essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) (MPNs) - have recently been shown to be associated with chronic inflammation, oxidative stress and accumulation of reactive oxygen species (ROS). Using whole blood transcriptional profiling, we report that several oxidative stress and anti-oxidative stress genes are significantly deregulated in MPNs. Among the twenty most up- and downregulated genes, ATOX1, DEFB122, GPX8, PRDX2, PRDX6, PTGS1, and SEPP1 were progressively upregulated from ET over PV to PMF, whereas AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively downregulated in ET, PV and PMF (all FDR <0.05). The gene Nrf2, encoding the transcription factor nuclear factor erythroid 2-related factor 2 (NFE2L2 or Nrf2) was significantly downregulated in all MPNs. Nrf2 has a key role in the regulation of the oxidative stress response and modulates both migration and retention of hematopoietic stem cells (HSCs) in their niche. The patogenetic importance of Nrf2 depletion in the context of expansion of the hematopoietic progenitor pool in MPNs is discussed with particular focus upon the implications of concomitant downregulation of Nrf2 and CXCR4 for stem cell mobilization.
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Affiliation(s)
- Hans Carl Hasselbalch
- Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark
- * E-mail:
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | | | - Lasse Kjær
- Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark
| | | | - Morten K. Jensen
- Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark
| | - Ole Weis Bjerrum
- Department of Hematology L, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Torben A. Kruse
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Vibe Skov
- Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark
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Zhang Z, Fye S, Borecki IB, Rader JS. Polymorphisms in immune mediators associate with risk of cervical cancer. Gynecol Oncol 2014; 135:69-73. [PMID: 25127987 PMCID: PMC4198466 DOI: 10.1016/j.ygyno.2014.07.106] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 07/26/2014] [Accepted: 07/28/2014] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The immune system is critical for controlling the progression of HPV cervical disease and the development of cancer. This study aimed to identify cervical cancer susceptibility alleles in candidate immune-modulating genes. METHODS Our family-based study involved a cohort of 641 probands (women with ICC/CIN III) and their biologic parents or siblings (641 trios). In the discovery phase (stage 1), involving 288 of the trios, 80 tag single nucleotide polymorphisms (SNPs) in 11 immune-modulating genes (IFNG, IFNGR1, IFNGR2, JAK1, JAK2, STAT1, STAT6, IL12A, TNF, LTA and LTB) were evaluated on the GoldenGate platform. We used the combined dataset for a total of 641 trios (stage 2) and the Taqman platform to validate the SNPs that had proved significant in the discovery dataset. The transmission disequilibrium test was used to detect significant shifts in allelic transmissions in the datasets. RESULTS Two SNPs in JAK2 and one SNP in STAT6 showed significant allelic association with cervical cancer in the stage 1 discovery dataset and were replicated in the larger joint analysis stage 2 dataset (JAK2 rs10815144, P=0.0029 and rs12349785, P=0.0058; and STAT6 rs3024971, P=0.0127). An additional SNP in exon 19 of JAK2 (rs2230724) was also examined in the combined dataset due to its strong linkage disequilibrium (LD) with rs10815144. It was also significant (P=0.0335). CONCLUSIONS Our results suggest an association of SNPs in JAK2 and STAT6 with cervical cancer. This association should be investigated in additional cervical cancer populations.
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Affiliation(s)
- Zhengyan Zhang
- Washington University School of Medicine in St. Louis, 660 South Euclid Ave., St. Louis, MO 63011, USA
| | - Samantha Fye
- Medical College of Wisconsin, 9200W. Wisconsin Ave., Milwaukee, WI 53226, USA
| | - Ingrid B Borecki
- Washington University School of Medicine in St. Louis, 660 South Euclid Ave., St. Louis, MO 63011, USA
| | - Janet S Rader
- Medical College of Wisconsin, 9200W. Wisconsin Ave., Milwaukee, WI 53226, USA.
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46
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Genetic effects of single nucleotide polymorphisms in JAK2 and STAT5A genes on susceptibility of Chinese Holsteins to mastitis. Mol Biol Rep 2014; 41:8293-301. [PMID: 25205126 DOI: 10.1007/s11033-014-3730-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 09/03/2014] [Indexed: 02/06/2023]
Abstract
The JAK-STAT pathway plays a key role in host immunity. The present study was designed to evaluate the effects of single nucleotide polymorphisms (SNPs) in STAT5A and JAK2 genes on some serum cytokines, mastitis and milk production traits. Two SNPs (SNP1 43046497A/C and SNP2 43047829G/A) in STAT5A, and four SNPs in JAK2 (SNP3 39652267A/G, SNP4 39630048C/T, SNP5 39631044G/A, and SNP6 39631175T/C) were revealed and genotyped in 268 Chinese Holstein cattle. Fixed model was used to analyze the association of SNPs with phenotypes by general linear model procedure of SAS 9.1. SNP1 and SNP4 were significantly associated with IL-6 and IL-17 (P < 0.05), respectively. In JAK2 gene, SNP3 was highly significant (P < 0.01) and SNP5 was significant (P < 0.05) in association with SCC, whereas, the association of SNP6 was found significant (P < 0.05) with both SCC and SCS. Combination genotype analysis revealed that SNPs in JAK2 gene significantly associated with SCC and SCS were associated significantly with the corresponding phenotypes in combinations as well. The GG genotype of SNP3 individually and in any combination genotypes showed lowest SCC. The dominant effect of SNP1, SNP5 and SNP6 was found highly significant (P < 0.01) on the corresponding phenotypes (IL-6, SCC and SCS). As for haplotype analysis, two haplotypes were revealed between the two SNPs of STAT5A gene and four haplotypes amongst four SNPs in JAK2 gene; strong linkage disequilibrium (D' > 0.9) was observed between all these haplotypes. The results imply that the identified SNPs could be powerful markers to select dairy cattle with improved genetic resistance against mastitis.
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48
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The JAK2 46/1 haplotype (GGCC) in myeloproliferative neoplasms and splanchnic vein thrombosis: a pooled analysis of 26 observational studies. Ann Hematol 2014; 93:1845-52. [DOI: 10.1007/s00277-014-2134-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 06/03/2014] [Indexed: 12/20/2022]
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49
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Nauroy P, Delhommeau F, Baklouti F. JAK2V617F mRNA metabolism in myeloproliferative neoplasm cell lines. Blood Cancer J 2014; 4:e222. [PMID: 24972151 PMCID: PMC4080214 DOI: 10.1038/bcj.2014.43] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- P Nauroy
- mRNA Metabolism in Normal and Pathological Cells, CNRS UMR 5534, Université Lyon 1, Villeurbanne, France
| | - F Delhommeau
- 1] Sorbonne Universités, UPMC Univ Paris 06, GRC no. 07, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MyPAC, Paris, France [2] AP-HP, Hôpital Saint-Antoine, Laboratoire d'Hématologie, Paris, France [3] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France [4] INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France
| | - F Baklouti
- mRNA Metabolism in Normal and Pathological Cells, CNRS UMR 5534, Université Lyon 1, Villeurbanne, France
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50
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Hasselbalch HC. The role of cytokines in the initiation and progression of myelofibrosis. Cytokine Growth Factor Rev 2013; 24:133-45. [DOI: 10.1016/j.cytogfr.2013.01.004] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 01/09/2013] [Indexed: 12/21/2022]
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