• Humans
• Interferon-alpha/therapeutic use
• Interferon-alpha/pharmacology
• Polycythemia Vera/drug therapy
• Polycythemia Vera/genetics
• Polycythemia Vera/pathology
• Polycythemia Vera/metabolism
• Male
• Janus Kinase 2/genetics
• Female
• Mutation

• Humans
• Interferon-alpha/therapeutic use
• Polycythemia Vera/drug therapy
• Polycythemia Vera/pathology
• Polycythemia Vera/therapy
• Primary Myelofibrosis/drug therapy
• Polyethylene Glycols/therapeutic use
• Thrombocythemia, Essential/drug therapy
• Thrombocythemia, Essential/genetics
• Female
• Pregnancy
• Recombinant Proteins/therapeutic use
• Interferon alpha-2/therapeutic use

• Humans
• Interferon-alpha/therapeutic use
• Interferon-alpha/administration & dosage
• Polycythemia Vera/drug therapy
• Polycythemia Vera/diagnosis
• Aged
• Male
• Female
• Nitriles/therapeutic use
• Pyrazoles/therapeutic use
• Pyrazoles/administration & dosage
• Middle Aged
• Polyethylene Glycols/therapeutic use
• Recombinant Proteins/therapeutic use
• Pyrimidines/therapeutic use
• Janus Kinase 2/genetics
• Treatment Outcome
• Aged, 80 and over

• Asian
• hematological responses
• molecular responses
• myeloproliferative neoplasm
• polycythemia vera
• ropeginterferon alpha‐2b
• single nucleotide polymorphisms

• Humans
• Neoplasms
• Myeloproliferative Disorders/drug therapy
• Myeloproliferative Disorders/genetics
• Treatment Outcome
• Haplotypes
• Germ Cells
• Interferon Lambda
• Interleukins/genetics

• COPRG6K0023 Chiayi Chang Gung Memorial Hospital
• CORPG6K0013 Chiayi Chang Gung Memorial Hospital
• DOH-102-TD-C-111-006 Chang Gung Memorial Hospital, Linkou
• NSTC112-2314-B-182-055 Chang Gung Memorial Hospital, Linkou
• XPRPG3H0011-16 Chang Gung Memorial Hospital, Linkou
• Chiayi Chang Gung Memorial Hospital
• Chang Gung Memorial Hospital, Linkou

• DNA damage
• antioxidant
• clinical trials
• genomic instability
• hematological malignancy
• in vitro
• in vivo
• leukemia
• natural substances
• polyphenols
• telomerase
• vitamins

• acute myeloid leukemia
• antileukemic immunity
• aplastic anemia
• inflammatory stressors
• leukemic transformation
• myelodysplastic syndrome

• Humans
• Anemia, Aplastic/therapy
• Bone Marrow
• Myelodysplastic Syndromes/genetics
• Myeloproliferative Disorders
• Leukemia, Myeloid, Acute/genetics

• JAK inhibitor
• epigenetic regulation
• molecular diagnostics
• mutations
• myelofibrosis
• myeloproliferative neoplasm
• next-generation sequencing
• primary myelofibrosis

• haematopoietic stem cells
• cell signalling

• Humans
• Mice
• Animals
• Tumor Suppressor Protein p53/genetics
• Janus Kinase 2/genetics
• Janus Kinase 2/metabolism
• Myeloproliferative Disorders/drug therapy
• Myeloproliferative Disorders/genetics
• Mutation
• Interferon-alpha/pharmacology
• Leukemia, Myeloid, Acute
• Genomics

• DNA hypomethylating agents
• DNA methylation
• interferon response
• leukaemia stem cells
• myeloproliferative neoplasm
• secondary acute myeloid leukaemia
• viral mimicry

• Humans
• Animals
• Mice
• Myeloproliferative Disorders/drug therapy
• Myeloproliferative Disorders/genetics
• Myeloproliferative Disorders/complications
• Leukemia, Myeloid, Acute/drug therapy
• Leukemia, Myeloid, Acute/genetics
• Leukemia, Myeloid, Acute/pathology
• Prognosis
• Biomarkers
• Interferons/therapeutic use

• 489073 Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada
• Elizabeth and Tony Comper MPN Program at Princess Margaret Cancer Centre
• 2015/21237-4 Fundação de Amparo à Pesquisa do Estado de São Paulo
• 2015/21866-1 Fundação de Amparo à Pesquisa do Estado de São Paulo
• 2017/03019-5 Fundação de Amparo à Pesquisa do Estado de São Paulo
• Guglietti Fellowship PMC Foundation
• Hold'em for life Post-doctoral fellowship
• 201512MSH-360794-228629 Institute of Cancer Research
• 148430 Institute of Cancer Research
• Instituto Nacional de Ciência e Tecnologia da Criosfera
• Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Ontario Institute for Cancer Research (OICR)

• barriers to treatment
• current approach
• future perspectives
• polycythemia vera

• Essential Thrombocythemia
• Polycythemia Vera
• Primary Myelofibrosis
• myeloproliferative neoplasms
• ropeginterferon alfa-2b

• Humans
• Male
• Female
• Adolescent
• Young Adult
• Adult
• Middle Aged
• Polycythemia Vera/drug therapy
• Polycythemia Vera/genetics
• Philadelphia Chromosome
• Myeloproliferative Disorders/diagnosis
• Myeloproliferative Disorders/drug therapy
• Myeloproliferative Disorders/genetics
• Polyethylene Glycols/adverse effects
• Mutation

• Acute myeloid leukemia
• Aplastic anemia
• Case report
• Leukemic transformation
• Paroxysmal nocturnal hemoglobinuria
• Tuberculosis

Myelodysplastic syndrome (MDS) is caused by malignant proliferation and ineffective hematopoiesis. Oncogenic somatic mutations and increased apoptosis, necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells. An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage. Bone marrow cellularity and myeloblasts usually increase with disease progression. However, aplastic crisis occasionally occurs in advanced MDS.

A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1 (MDS-EB-1) based on an increase in the percentages of myeloblasts and cluster of differentiation (CD)34+ hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples. The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years. In the treatment process, the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia. During the aplastic crisis, the bone marrow was infiltrated with sparsely distributed atypical lymphocytes. Surprisingly, the leukemic cells disappeared. Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3, CD5, CD8, CD16, CD56 and CD57, suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer (NK)/NKT cells that suppressed both normal and leukemic hematopoiesis. Elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), confirmed the deranged type I immune responses. This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia. Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche. Antituberculosis treatment led to reversion of the aplastic crisis, disappearance of the atypical lymphocytes, increased marrow cellularity and 2 mo of hematological remission, providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis, the regression of leukemic cells and the activation of CD56+ atypical lymphocytes. Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state. However, the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode.

Disseminated tuberculosis can induce CD56+ lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis, resulting in the development of aplastic crisis and leukemic cell regression.

• Myelodysplastic syndrome
• Aplastic crisis
• Atypical lymphocyte
• Leukemic cell regression
• CD56+ lymphocyte expansion
• Disseminated tuberculosis
• Case report

Myelodysplastic syndrome (MDS) is a hematological neoplasm, and an increase in myeloblasts is representative of leukemic hematopoiesis in advanced MDS. Low-risk MDS usually exhibits deranged autoimmunity resembling that of aplastic anemia (AA), whereas advanced MDS is characterized by a phenotype of immune exhaustion. MDS can be normo/hyperplastic or hypoplastic. Generally, bone marrow cellularity and myeloblasts increase with disease progression. Transformation from advanced MDS to AA-like syndrome with leukemic cell regression has not previously been reported.

A middle-aged Chinese woman had a 4-year history of leukocytopenia. Six months prior to admission, the patient developed gradually worsening fatigue and performance status. The leukocytopenia further progressed. She was diagnosed with MDS with excess blasts-2 based on increased bone marrow cellularity and an increased percentage of myeloblasts on marrow and blood smears, an increased percentage of cluster of differentiation (CD)34+CD33+ progenitors in immunotyping analysis, a normal karyotype in cytogenetic analysis, and the identification of somatic mutations in CBL, KMT2D and NF1 in molecular analysis. Initially, neutropenia was the predominant hematological abnormality, with mild anemia and thrombocytosis, and the degree of fatigue was far more severe than the degree of anemia. In the following months, the patient experienced several febrile episodes. Intravenous antibiotic treatments were able to control the febrile episodes, but the elevated inflammatory indices persisted. The hematological parameters dramatically fluctuated with the waxing and waning of the inflammatory episodes. With recurrent flares of the inflammatory condition, agranulocytosis and severe anemia developed, with mild thrombocytopenia. During the patient’s hospitalization, computed tomography (CT) scans revealed the presence of extensive inflammatory lesions involving the lungs, mediastinum, pleura, gastrointestinal tract, peritoneum and urinary tract, with imaging features suggestive of the reactivation of disseminated tuberculosis. Reevaluation of the bone marrow smears revealed that the cellularity became hypoplastic, and the leukemic cells regressed, suggesting that both normal and leukemic hematopoiesis had been heavily suppressed. Immunological analysis of the bone marrow samples revealed a decreased percentage of CD34+ cells and an immunological signature resembling that of severe AA (SAA), confirming the regression of the leukemic cells by autoimmune-mediated attacks. The patient demonstrated resistance to multiple drugs, including antituberculotics, recombinant human granulocyte colony-stimulating factor, broad-spectrum antibiotics, voriconazole, ganciclovir, immune suppressants, eltrombopag and intravenous immunoglobulin, which further worsened the hematological injury and patient’s performance status. The patient eventually died of overwhelming infection and multidrug resistance.

Advanced MDS can transform to aplastic cytopenia with leukemic cell regression and an immunological signature of SAA during inflammatory flare-ups.

• Myelodysplastic syndrome
• Aplastic anemia
• Inflammatory stress
• Leukemic cell regression
• Antileukemic
• Case report

• Humans
• Polycythemia Vera
• Polycythemia
• Thrombocytosis
• Thrombosis
• Leukocytosis

• aggregation-induced emission
• immunogenic cell death
• multiple myeloma
• photodynamic therapy
• reactive oxygen species

• Humans
• Neoplasms/therapy
• Immunogenic Cell Death
• Endoplasmic Reticulum Stress
• Antineoplastic Agents/therapeutic use
• Hematologic Neoplasms/drug therapy
• Tumor Microenvironment

• 81900131 National Natural Science Foundation of China
• 82000219 National Natural Science Foundation of China
• 8210010129 National Natural Science Foundation of China Youth Project
• 18JCQNJC80400 Tianjin Municipal Natural Science Foundation
• 19JCZDJC32900 Tianjin Municipal Natural Science Foundation
• 2018KJ043 Tianjin Education Commission Research Project
• 20140118 Tianjin Education Commission Research Project
• 2018KJ045 Tianjin Education Commission Research Project
• 20YFZCSY00060 Tianjin Science and Technology Planning Project
• TJWJ2021QN001 Tianjin Municipal Health Commission Youth Project
• MJR20221011 Medjaden Academy and Research Foundation for Young Scientists
• TJYXZDXK-028A Tianjin Key Medical Discipline (Specialty) Construction project
• National Natural Science Foundation of China

• Essential Thrombocythaemia
• IFN
• MPN
• Polycythaemia Vera

• MPN
• MPNs
• essential thrombocythemia
• myelofibrosis
• myeloproliferative neoplasms
• polycythemia vera
• recombinant interferon-α2 (rIFN-α2)
• recombinant interferon-β (rIFN-β)

• Animals
• Carbonic Anhydrases
• Hematologic Neoplasms/pathology
• Hematopoietic Stem Cells
• Janus Kinase 2/genetics
• Mice
• Polycythemia Vera/drug therapy

Myeloproliferative neoplasms (MPN) are chronic cancers of the hematopoietic stem cells in the bone marrow, and patients often harbor elevated numbers of circulating platelets (PLT). We investigated the frequencies of circulating PLT-lymphocyte aggregates in MPN patients and the effect of PLT-binding on CD8 T cell function. The phenotype of these aggregates was evaluated in 50 MPN patients and 24 controls, using flow cytometry. In vitro studies compared the proliferation, cytokine release, and cytoxicity of PLT-bound and PLT-free CD8 T cells. Frequencies of PLT-CD8 T cell aggregates, were significantly elevated in MPN patients. Advanced disease stage and CALR mutation associated with the highest aggregate frequencies with a predominance of PLT-binding to antigen-experienced CD8 T cells. PLT-bound CD8 T cells showed reduction in proliferation and cytotoxic capacity. Our data suggest that CD8 T cell responses are jeopardized in MPN patients. JAK2 and CALR exon 9 mutations – the two predominant driver mutations in MPN – are targets for natural T cell responses in MPN patients. Moreover, MPN patients have more infections compared to background. Thus, PLT binding to antigen experienced CD8 T cells could play a role in the inadequacy of the immune system to control MPN disease progression and prevent recurrent infections.

• CALR mutation
• JAK2 mutation
• Myeloproliferative Neoplasms (MPN)
• platelet-T cell aggregates
• platelet-bound T cells
• platelets

• National Natural Science Foundation of China

• Chronic myelogenous leukemia (CML)
• Death receptors
• Kaempferol
• Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)
• cFLIP
• cIAP

Interferon α (IFNα) is used to treat JAK2^V617F-driven myeloproliferative neoplasms (MPNs) but rarely clears the disease. We investigated the IFNα mechanism of action focusing on PML, an interferon target and key senescence gene whose targeting by arsenic trioxide (ATO) drives eradication of acute promyelocytic leukemia. ATO sharply potentiated IFNα-induced growth suppression of JAK2^V617F patient or mouse hematopoietic progenitors, which required PML and was associated with features of senescence. In a mouse MPN model, combining ATO with IFNα enhanced and accelerated responses, eradicating MPN in most mice by targeting disease-initiating cells. These results predict potent clinical efficacy of the IFNα+ATO combination in patients and identify PML as a major effector of therapy, even in malignancies with an intact PML gene.

NK cells are important innate immune effectors that contribute substantially to tumor control, however the role of NK cells in haematological cancers is not as well understood. The aim of this review is to highlight the importance of the role of NK cells in the management of Ph+ Myeloproliferative Neoplasms, and emphasize the need and possible benefits of a more in-depth investigation into their role in classical MPNs and show potential strategies to harness the anti-tumoral capacities of NK cells.

Myeloproliferative neoplasms (MPNs) comprise a heterogenous group of hematologic neoplasms which are divided into Philadelphia positive (Ph+), and Philadelphia negative (Ph−) or classical MPNs. A variety of immunological factors including inflammatory, as well as immunomodulatory processes, closely interact with the disease phenotypes in MPNs. NK cells are important innate immune effectors and substantially contribute to tumor control. Changes to the absolute and proportionate numbers of NK cell, as well as phenotypical and functional alterations are seen in MPNs. In addition to the disease itself, a variety of therapeutic options in MPNs may modify NK cell characteristics. Reports of suppressive effects of MPN treatment strategies on NK cell activity have led to intensive investigations into the respective compounds, to elucidate the possible negative effects of MPN therapy on control of the leukemic clones. We hereby review the available literature on NK cells in Ph+ and Ph− MPNs and summarize today’s knowledge on disease-related alterations in this cell compartment with particular focus on known therapy-associated changes. Furthermore, we critically evaluate conflicting data with possible implications for future projects. We also aim to highlight the relevance of full NK cell functionality for disease control in MPNs and the importance of considering specific changes related to therapy in order to avoid suppressive effects on immune surveillance.

• CML
• Innate immunity
• essential thrombocythemia
• polycythemia vera
• primary myelofibrosis

• Cytokines
• Diabetic retinopathy
• Inflammation
• Interferon-alpha
• Interferon-gamma
• Interferons

• Animals
• Hematopoietic Stem Cells/physiology
• Humans
• Signal Transduction/physiology
• Stem Cells/physiology

• Essential thrombocythemia
• Hematological response
• Interferon
• Molecular response
• Polycythemia vera

• Biomarkers
• Cell Transformation, Neoplastic
• Disease Management
• Disease Progression
• Hematologic Tests
• Humans
• Interferons/pharmacology
• Interferons/therapeutic use
• Polycythemia Vera/diagnosis
• Polycythemia Vera/drug therapy
• Polycythemia Vera/etiology
• Prognosis
• Publication Bias
• Thrombocythemia, Essential/diagnosis
• Thrombocythemia, Essential/drug therapy
• Thrombocythemia, Essential/etiology
• Treatment Outcome

Myeloid neoplasms, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), feature clonal dominance and remodeling of the bone marrow niche in a manner that promotes malignant over non-malignant hematopoiesis. This take-over of hematopoiesis by the malignant clone is hypothesized to include hyperactivation of inflammatory signaling and overproduction of inflammatory cytokines. In the Ph-negative MPNs, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation of polycythemia vera (PV) or essential thrombocythemia (ET) to secondary myelofibrosis (MF), and the equivalent emergence of primary myelofibrosis (PMF). Bone marrow fibrosis itself is thought to be mediated heavily by the cytokine TGF-β, and possibly other cytokines produced as a result of hyperactivated JAK2 kinase in the malignant clone. MF also features extramedullary hematopoiesis and progression to bone marrow failure, both of which may be mediated in part by responses to cytokines. In MF, elevated levels of individual cytokines in plasma are adverse prognostic indicators: elevated IL-8/CXCL8, in particular, predicts risk of transformation of MF to secondary AML (sAML). Tumor necrosis factor (TNF, also known as TNFα), may underlie malignant clonal dominance, based on results from mouse models. Human PV and ET, as well as MF, harbor overproduction of multiple cytokines, above what is observed in normal aging, which can lead to cellular signaling abnormalities separate from those directly mediated by hyperactivated JAK2 or MPL kinases. Evidence that NFκB pathway signaling is frequently hyperactivated in a pan-hematopoietic pattern in MPNs, including in cells outside the malignant clone, emphasizes that MPNs are pan-hematopoietic diseases, which remodel the bone marrow milieu to favor persistence of the malignancy. Clinical evidence that JAK2 inhibition by ruxolitinib in MF neither reliably reduces malignant clonal burden nor eliminates cytokine elevations, suggests targeting cytokine mediated signaling as a therapeutic strategy, which is being pursued in new clinical trials. Greater knowledge of inflammatory pathophysiology in MPNs can therefore contribute to the development of more effective therapy.

• JAK2
• NF kappa B (NFκB)
• Ruxolitinib
• cytokines
• intracellular signaling
• myelofibrosis
• myeloproliferative neoplasms
• tumor necrosis factor (TNF)

• BRAF inhibitors
• Drug toxicity
• MEK inhibitors
• anticancer drugs
• conventional chemotherapy
• immunotherapy
• ocular adverse effects
• retinal toxicity
• targeted agents

• CMML
• MPN
• dCMML
• pCMML

• givinostat
• interferon
• polycythemia vera
• ruxolitinib
• therapy

• JAK2V617F
• MPN
• hematopoietic stem cells
• heterogeneity
• inflammation
• interferon
• megakaryocyte lineage priming
• pathogenesis
• single cell RNA-Seq
• therapeutic response

• Hematopoietic Stem Cells
• Humans
• Janus Kinase 2
• Mutation/genetics
• Myeloproliferative Disorders/drug therapy
• Neoplasms
• Polycythemia Vera/drug therapy
• Polycythemia Vera/genetics

• 21762 Cancer Research UK
• MC_PC_17230 Medical Research Council

There is growing evidence that Ph-negative myeloproliferative neoplasms are disorders in which multiple signaling pathways are significantly disturbed. The heterogeneous phenotypes observed among patients have highlighted the importance of having a comprehensive knowledge of the molecular mechanisms behind these diseases. This review aims to show a broad overview of the signaling involved in myeloproliferative neoplasms (MPNs) and other processes that can modify them, which could be helpful to better understand these diseases and develop more effective targeted treatments.

Ph-negative myeloproliferative neoplasms (polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)) are infrequent blood cancers characterized by signaling aberrations. Shortly after the discovery of the somatic mutations in JAK2, MPL, and CALR that cause these diseases, researchers extensively studied the aberrant functions of their mutant products. In all three cases, the main pathogenic mechanism appears to be the constitutive activation of JAK2/STAT signaling and JAK2-related pathways (MAPK/ERK, PI3K/AKT). However, some other non-canonical aberrant mechanisms derived from mutant JAK2 and CALR have also been described. Moreover, additional somatic mutations have been identified in other genes that affect epigenetic regulation, tumor suppression, transcription regulation, splicing and other signaling pathways, leading to the modification of some disease features and adding a layer of complexity to their molecular pathogenesis. All of these factors have highlighted the wide variety of cellular processes and pathways involved in the pathogenesis of MPNs. This review presents an overview of the complex signaling behind these diseases which could explain, at least in part, their phenotypic heterogeneity.

• CALR
• JAK2
• MPL
• TPOR
• myeloproliferative neoplasms
• signaling pathways

The calreticulin (CALR) exon 9 mutations that are identified in 20% of patients with Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) generate immunogenic antigens. Thus, therapeutic cancer vaccination against mutant CALR could be a new treatment modality in CALR-mutant MPN.

The safety and efficacy of vaccination with the peptide CALRLong36 derived from the CALR exon 9 mutations was tested in a phase I clinical vaccination trial with montanide as adjuvant. Ten patients with CALRmut MPN were included in the trial and received 15 vaccines over the course of one year. The primary end point was evaluation of safety and toxicity of the vaccine. Secondary endpoint was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT03566446).

Patients had a median age of 59.5 years and a median disease duration of 6.5 years. All patients received the intended 15 vaccines, and the vaccines were deemed safe and tolerable as only two grade three AE were detected, and none of these were considered to be related to the vaccine. A decline in platelet counts relative to the platelets counts at baseline was detected during the first 100 days, however this did not translate into neither a clinical nor a molecular response in any of the patients. Immunomonitoring revealed that four of 10 patients had an in vitro interferon (IFN)-γ ELISPOT response to the CALRLong36 peptide at baseline, and four additional patients displayed a response in ELISPOT upon receiving three or more vaccines. The amplitude of the immune response increased during the entire vaccination schedule for patients with essential thrombocythemia. In contrast, the immune response in patients with primary myelofibrosis did not increase after three vaccines.

Therapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable. The vaccines did not induce any clinical responses. However, the majority of patients displayed a marked T-cell response to the vaccine upon completion of the trial. This suggests that vaccines directed against mutant CALR may be used with other cancer therapeutic modalities to enhance the anti-tumor immune response.

• calreticulin
• cancer immune therapy
• cancer vaccines
• myeloproliferative neoplasms
• neo-antigen

• Myeloproliferative neoplasms
• anagrelide
• essential thrombocythemia
• hydroxyurea
• interferon
• polycythemia vera
• primary myelofibrosis
• ruxolitinib