|
1
|
Elbaz Younes I, Mroz P, Tashakori M, Hamed A, Sen S. Chronic Neutrophilic Leukemia: Advances in Diagnosis, Genetic Insights, and Management Strategies. Cancers (Basel) 2025; 17:227. [PMID: 39858009 PMCID: PMC11763460 DOI: 10.3390/cancers17020227] [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: 11/15/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
CNL is a rare subtype of MPNs characterized by persistent neutrophilia, bone marrow hypercellularity, and specific genetic mutations, particularly in the CSF3R gene. Advances in molecular diagnostics have greatly enhanced our understanding of CNL, distinguishing it from other myeloproliferative disorders and refining diagnostic criteria. This review provides an updated overview of CNL, focusing on breakthroughs in genetic profiling, including novel mutations with potential prognostic value and implications for targeted therapy. We discuss current management strategies, emphasizing the role of JAK inhibitors, allogeneic stem cell transplantation, and evolving investigational treatments. Challenges in early diagnosis, therapeutic resistance, and future directions in research are also addressed, underscoring the need for a personalized medicine approach to improve outcomes for patients with CNL.
Collapse
Affiliation(s)
- Ismail Elbaz Younes
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA; (P.M.); (M.T.); (A.H.); (S.S.)
| | | | | | | | | |
Collapse
|
|
2
|
Han Y, Shi Y, Wu T, Zhou J. CSF3R Gln776X and ASXL1 mutations in multiple myeloma associated with chronic neutrophilic leukemia: case report and literature review. Arch Med Sci 2024; 20:2090-2093. [PMID: 39967925 PMCID: PMC11831355 DOI: 10.5114/aoms/199530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Affiliation(s)
- Ying Han
- 940 Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, China
| | - Yajun Shi
- 940 Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, China
| | - Tao Wu
- 940 Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, China
| | - Jinmao Zhou
- 940 Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, China
| |
Collapse
|
|
3
|
Cao S, Tao Q, Wang J, Zhang Q, Dong Y. Genetic Response of Chronic Neutrophilic Leukemia With CSF3R T618I, SETBP1, and ASXL1 Mutations After Decitabine Therapy. Am J Ther 2024; 31:e550-e552. [PMID: 39292831 DOI: 10.1097/mjt.0000000000001411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Susu Cao
- Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui, P.R. China
| | | | | | | | | |
Collapse
|
|
4
|
Gao J, Han S, Deng B, Deng Y, Gao X. Research progress of additional pathogenic mutations in chronic neutrophilic leukemia. Ann Hematol 2024; 103:2591-2600. [PMID: 37993585 DOI: 10.1007/s00277-023-05550-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 11/13/2023] [Indexed: 11/24/2023]
Abstract
Chronic neutrophilic leukemia (CNL) is a rare type of myeloproliferative neoplasm (MPN). Due to its nonspecific clinical symptoms and lack of specific molecular markers, it was previously difficult to distinguish it from other diseases with increased neutrophils. However, the discovery of the CSF3R mutation in CNL 10 years ago and the update of the diagnostic criteria by the World Health Organization (WHO) in 2016 brought CNL into a new era of molecular diagnosis. Next-generation sequencing (NGS) technology has led to the identification of numerous mutant genes in CNL. While CSF3R is commonly recognized as the driver mutation of CNL, other mutations have also been detected in CNL using NGS, including mutations in other signaling pathway genes (CBL, JAK2, NARS, PTPN11) and chromatin modification genes (ASXL1, SETBP1, EZH2), DNA methylation genes (DNMT3A, TET2), myeloid-related transcription factor genes (RUNX1, GATA2), and splicing and RNA metabolism genes (SRSF2, U2AF1). The coexistence of these mutated genes and CSF3R mutations, as well as the different evolutionary sequences of clones, deepens the complexity of CNL molecular biology. The purpose of this review is to summarize the genetic research findings of CNL in the last decade, focusing on the common mutated genes in CNL and their clinical significance, as well as the clonal evolution pattern and sequence of mutation acquisition in CNL, to provide a basis for the appropriate management of CNL patients.
Collapse
Affiliation(s)
- Jiapei Gao
- Department of Hematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Shuai Han
- Yangzhou University Medical College, Yangzhou, Jiangsu Province, China
| | - Bin Deng
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Yifan Deng
- Yangzhou University Medical College, Yangzhou, Jiangsu Province, China
| | - Xiaohui Gao
- Department of Hematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province, China.
| |
Collapse
|
|
5
|
Szuber N, Orazi A, Tefferi A. Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management. Am J Hematol 2024; 99:1360-1387. [PMID: 38644693 DOI: 10.1002/ajh.27321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 03/18/2024] [Indexed: 04/23/2024]
Abstract
Chronic neutrophilic leukemia (CNL) is a rare BCR::ABL1-negative myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis and bone marrow granulocyte hyperplasia. Atypical chronic myeloid leukemia (aCML) (myelodysplastic "[MDS]/MPN with neutrophilia" per World Health Organization [WHO]) is a MDS/MPN overlap disorder featuring dysplastic neutrophilia and circulating myeloid precursors. Both manifest with frequent hepatosplenomegaly and less commonly, bleeding, with high rates of leukemic transformation and death. The 2022 revised WHO classification conserved CNL diagnostic criteria of leukocytosis ≥25 × 109/L, neutrophils ≥80% with <10% circulating precursors, absence of dysplasia, and presence of an activating CSF3R mutation. ICC criteria are harmonized with those of other myeloid entities, with a key distinction being lower leukocytosis threshold (≥13 × 109/L) for cases CSF3R-mutated. Criteria for aCML include leukocytosis ≥13 × 109/L, dysgranulopoiesis, circulating myeloid precursors ≥10%, and at least one cytopenia for MDS-thresholds (ICC). In both classifications ASXL1 and SETBP1 (ICC), or SETBP1 ± ETNK1 (WHO) mutations can be used to support the diagnosis. Both diseases show hypercellular bone marrow due to a granulocytic proliferation, aCML distinguished by dysplasia in granulocytes ± other lineages. Absence of monocytosis, rare/no basophilia, or eosinophilia, <20% blasts, and exclusion of other MPN, MDS/MPN, and tyrosine kinase fusions, are mandated. Cytogenetic abnormalities are identified in ~1/3 of CNL and ~15-40% of aCML patients. The molecular signature of CNL is a driver mutation in colony-stimulating factor 3 receptor-classically T618I, documented in >80% of cases. Atypical CML harbors a complex genomic backdrop with high rates of recurrent somatic mutations in ASXL1, SETBP1, TET2, SRSF2, EZH2, and less frequently in ETNK1. Leukemic transformation rates are ~10-25% and 30-40% for CNL and aCML, respectively. Overall survival is poor: 15-31 months in CNL and 12-20 months in aCML. The Mayo Clinic CNL risk model for survival stratifies patients according to platelets <160 × 109/L (2 points), leukocytes >60 × 109/L (1 point), and ASXL1 mutation (1 point); distinguishing low- (0-1 points) versus high-risk (2-4 points) categories. The Mayo Clinic aCML risk model attributes 1 point each for: age >67 years, hemoglobin <10 g/dL, and TET2 mutation, delineating low- (0-1 risk factor) and high-risk (≥2 risk factors) subgroups. Management is risk-driven and symptom-directed, with no current standard of care. Most commonly used agents include hydroxyurea, interferon, Janus kinase inhibitors, and hypomethylating agents, though none are disease-modifying. Hematopoietic stem cell transplant is the only potentially curative modality and should be considered in eligible patients. Recent genetic profiling has disclosed CBL, CEBPA, EZH2, NRAS, TET2, and U2AF1 to represent high-risk mutations in both entities. Actionable mutations (NRAS/KRAS, ETNK1) have also been identified, supporting novel agents targeting involved pathways. Preclinical and clinical studies evaluating new drugs (e.g., fedratinib, phase 2) and combinations are detailed.
Collapse
MESH Headings
- Humans
- Leukemia, Neutrophilic, Chronic/genetics
- Leukemia, Neutrophilic, Chronic/diagnosis
- Leukemia, Neutrophilic, Chronic/therapy
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/diagnosis
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/therapy
- Mutation
- Risk Assessment
- Receptors, Colony-Stimulating Factor/genetics
- Carrier Proteins
- Nuclear Proteins
Collapse
Affiliation(s)
- Natasha Szuber
- Department of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
| | - Attilio Orazi
- Department of Pathology, Texas Tech University Health Sciences Center, El Paso, Texas, USA
| | - Ayalew Tefferi
- Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
6
|
Rakez R, Charef O, Boufrikha W, Rassas S, Boukhriss S, Laatiri MA. Autoimmune hemolytic anemia complicating a chronic neutrophilic leukemia: A case report of a rare association. Clin Case Rep 2023; 11:e7432. [PMID: 37251749 PMCID: PMC10220385 DOI: 10.1002/ccr3.7432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 05/10/2023] [Accepted: 05/15/2023] [Indexed: 05/31/2023] Open
Abstract
Key Clinical Message Chronic neutrophilic leukemia is a rare disease with a poor prognosis. Its diagnosis is challenging in the lack of genetic tools. It can infrequently be associated with autoimmune hemolytic anemia. Abstract Chronic neutrophilic leukemia is a rare disease with poor prognosis, characterized by a sustained mature neutrophilic leukocytosis in the absence of monocytosis or basophilia with few or no circulating immature granulocytes, hepatosplenomegaly, and granulocytic hyperplasia of the bone marrow. In addition, no molecular markers for other myeloproliferative neoplasms are detected. The 2016 WHO classification included the presence of the CSF3R mutation as a key diagnostic criterion for this disease. Although anemia may be present at diagnosis, hemolytic one rarely complicates myeloproliferative neoplasms. Treatment is largely based on cytoreductive agents, but bone marrow allograft remains the only curative option. We report the case of a patient with chronic neutrophilic leukemia associated with autoimmune hemolytic anemia. We describe the epidemiological, clinical, prognostic, and therapeutic features of this disease in addition to the difficulties of its diagnosis and management in Tunisia.
Collapse
Affiliation(s)
- Rim Rakez
- Department of HematologyFattouma Bourguiba Hospital of MonastirMonastirTunisia
| | - Ons Charef
- Department of HematologyFattouma Bourguiba Hospital of MonastirMonastirTunisia
| | - Wiem Boufrikha
- Department of HematologyFattouma Bourguiba Hospital of MonastirMonastirTunisia
| | - Syrin Rassas
- Department of HematologyFattouma Bourguiba Hospital of MonastirMonastirTunisia
| | - Sarra Boukhriss
- Department of HematologyFattouma Bourguiba Hospital of MonastirMonastirTunisia
| | | |
Collapse
|
|
7
|
Li N, Chen M, Yin CC. Advances in molecular evaluation of myeloproliferative neoplasms. Semin Diagn Pathol 2023; 40:187-194. [PMID: 37087305 DOI: 10.1053/j.semdp.2023.04.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/10/2023] [Accepted: 04/12/2023] [Indexed: 04/24/2023]
Abstract
Myeloproliferative neoplasms (MPN) are a group of clonal hematopoietic stem cell disorders with uncontrolled proliferation of one or more hematopoietic cell types, including myeloid, erythroid and megakaryocytic lineages, and minimal defect in maturation. Most MPN are associated with well-defined molecular abnormalities involving genes that encode protein tyrosine kinases that lead to constitutive activation of the downstream signal transduction pathways and confer cells proliferative and survival advantage. Genome-wide sequencing analyses have discovered secondary cooperating mutations that are shared by most of the MPN subtypes as well as other myeloid neoplasms and play a major role in disease progression. Without appropriate management, the natural history of most MPN consists of an initial chronic phase and a terminal blast phase. Molecular aberrations involving protein tyrosine kinases have been used for the diagnosis, classification, detection of minimal/measurable residual disease, and target therapy. We review recent advances in molecular genetic aberrations in MPN with a focus on MPN associated with gene rearrangements or mutations involving tyrosine kinase pathways.
Collapse
Affiliation(s)
- Nianyi Li
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mingyi Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
| | - C Cameron Yin
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
| |
Collapse
|
|
8
|
Thomopoulos TP, Symeonidis A, Kourakli A, Papageorgiou SG, Pappa V. Chronic Neutrophilic Leukemia: A Comprehensive Review of Clinical Characteristics, Genetic Landscape and Management. Front Oncol 2022; 12:891961. [PMID: 35494007 PMCID: PMC9048254 DOI: 10.3389/fonc.2022.891961] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 03/28/2022] [Indexed: 11/23/2022] Open
Abstract
Chronic neutrophilic leukemia (CNL) represents a rare disease, that has been classified among the BCR/ABL-negative myeloproliferative neoplasms. The disease is characterized by marked leukocytosis with absolute neutrophilia and its clinical presentation may vary from asymptomatic to highly symptomatic with massive splenomegaly and constitutional symptoms. CNL prognosis remains relatively poor, as most patients succumb to disease complications or transform to acute myeloid leukemia. Recent studies have demonstrated that CSF3R mutations drive the disease, albeit the presence of other secondary mutations perplex the genetic landscape of the disease. Notably, the presence of CSF3R mutations has been adopted as a criterion for diagnosis of CNL. Despite the vigorous research, the management of the disease remains suboptimal. Allogeneic stem cell transplantation represents the only treatment that could lead to cure; however, it is accompanied by high rates of treatment-related mortality. Recently, ruxolitinib has shown significant responses in patients with CNL; however, emergence of resistance might perturbate long-term management of the disease. The aim of this review is to summarize the clinical course and laboratory findings of CNL, highlight its pathogenesis and complex genetic landscape, and provide the context for the appropriate management of patients with CNL.
Collapse
Affiliation(s)
- Thomas P. Thomopoulos
- Second Department of Internal Medicine, Attikon Hospital, Research Institute, National and Kapodistrian University of Athens, Athens, Greece
| | - Argiris Symeonidis
- Department of Internal Medicine, University Hospital of Patras, Rio, Greece
| | - Alexandra Kourakli
- Department of Internal Medicine, University Hospital of Patras, Rio, Greece
| | - Sotirios G. Papageorgiou
- Second Department of Internal Medicine, Attikon Hospital, Research Institute, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasiliki Pappa
- Second Department of Internal Medicine, Attikon Hospital, Research Institute, National and Kapodistrian University of Athens, Athens, Greece
- *Correspondence: Vasiliki Pappa,
| |
Collapse
|
|
9
|
Szuber N, Elliott M, Tefferi A. Chronic neutrophilic leukemia: 2022 update on diagnosis, genomic landscape, prognosis, and management. Am J Hematol 2022; 97:491-505. [PMID: 35089603 DOI: 10.1002/ajh.26481] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 01/26/2022] [Indexed: 11/09/2022]
Abstract
DISEASE OVERVIEW Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. The 2013 seminal discovery of oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL not only established its molecular pathogenesis but provided a diagnostic biomarker and rationale for pharmacological targeting. DIAGNOSIS In 2016, the World Health Organization (WHO) recognized activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 109 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN. MANAGEMENT There is currently no standard of care for management of CNL, due in large part to the rarity of disease and dearth of formal clinical trials. Most commonly used therapeutic agents include conventional oral chemotherapy (e.g., hydroxyurea), interferon, and Janus kinase (JAK) inhibitors, while hematopoietic stem cell transplant remains the only potentially curative modality. DISEASE UPDATES Increasingly comprehensive genetic profiling in CNL, including new data on clonal evolution, has disclosed a complex genomic landscape with additional mutations and combinations thereof driving disease progression and drug resistance. Although accurate prognostic stratification and therapeutic decision-making remain challenging in CNL, emerging data on molecular biomarkers and the addition of newer agents, such as JAK inhibitors, to the therapeutic arsenal, are paving the way toward greater standardization and improvement of patient care.
Collapse
Affiliation(s)
- Natasha Szuber
- Department of Hematology Maisonneuve‐Rosemont Hospital Montreal Quebec Canada
| | - Michelle Elliott
- Division of Hematology, Department of Internal Medicine Mayo Clinic Rochester Minnesota USA
| | - Ayalew Tefferi
- Division of Hematology, Department of Internal Medicine Mayo Clinic Rochester Minnesota USA
| |
Collapse
|
|
10
|
Gao JP, Zhai LJ, Gao XH, Min FL. Chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance: A case report and literature review. J Clin Lab Anal 2022; 36:e24287. [PMID: 35170077 PMCID: PMC8993655 DOI: 10.1002/jcla.24287] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/31/2022] [Accepted: 02/01/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Study of the molecular biological characteristics of chronic neutrophilic leukemia complicated with plasma cell disorder (CNL-PCD) and lymphocytic proliferative disease (CNL-LPD). METHODS The clinical data of a patient with chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance (CNL-MGUS) in our hospital were reviewed, and the Chinese and/or English literature about CNL-PCD and CNL-LPD in PubMed and the Chinese database CNKI in the past 10 years was searched to analyze the molecular biological characteristics of this disease. RESULTS A 73-year-old male had persistent leukocytosis for 18 months. The white blood cell count was 46.77 × 109/L and primarily composed of mature neutrophils; hemoglobin: 77 g/L; platelet count: 189 × 109/L. Serum immunofixation electrophoresis showed IgG-λ monoclonal M protein. A CT scan showed splenomegaly. Next-generation sequencing (NGS) showed that CSF3R T618I, ASXL1 and RUNX1 mutations were positive. It was diagnosed as CNL-MGUS. We summarized 10 cases of CNL-PCD and 1 case of CNL-LPD who underwent genetic mutation detection reported in the literature. The CSF3R mutational frequency (7/11, 63.6%) was lower than that of isolated CNL. The ASXL1 mutations were all positive (3/3), which may represent a poor prognostic factor. The SETBP1 mutation may promote the progression of CNL-PCD. We also found JAK2, RUNX1, NRAS, etc. in CNL-PCD. CONCLUSIONS Chronic neutrophilic leukemia may be more inclined to coexist with plasma cell disorder. The CSF3R mutation in CNL-PCD is still the most common mutated gene compared with isolated CNL. Mutations in SETBP1 and ASXL1 may be poor prognostic factors for CNL-PCD.
Collapse
Affiliation(s)
- Jia-Pei Gao
- Department of Hematology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Li-Jia Zhai
- Department of Hematology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Xiao-Hui Gao
- Department of Hematology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Feng-Ling Min
- Department of Hematology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| |
Collapse
|
|
11
|
Abstract
OPINION STATEMENT Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R). Due in large part to the rarity of the disease and dearth of clinical trials, there is currently no standard of care for CNL. Available therapies range from conventional oral chemotherapy to targeted JAK inhibitors to hematopoietic stem cell transplant (HSCT), the latter representing the only potentially curative modality. For this reason, coupled with CNL's typically aggressive clinical course, allogeneic HSCT remains the primary recommended therapy for eligible patients. For ineligible patients, a number of nontransplant therapies have been evaluated in limited trials. These agents may additionally be considered "bridging" therapies pre-transplant in order to control myeloproliferation and alleviate symptoms. Historically, the most commonly utilized first-line agent has been hydroxyurea, though most patients ultimately require second (or subsequent)-line therapy; still hydroxyurea remains the conventional frontline option. Dasatinib has demonstrated efficacy in vitro in cases of CSF3R terminal membrane truncation mutations and may cautiously be considered upfront in such instances, though no substantive studies have validated its efficacy in vivo. Numerous other chemotherapy agents, practically re-appropriated from the pharmaceutical arsenal of MPN, have been utilized in CNL and are typically reserved for second/subsequent-line settings; these include interferon-alpha (IFN-a), hypomethylating agents, thalidomide, cladribine, and imatinib, among others. Most recently, ruxolitinib, a JAK1/2 inhibitor targeting JAK-STAT signaling downstream from CSF3R, has emerged as a potentially promising new candidate for the treatment of CNL. Increasingly robust data support the clinical efficacy, with associated variable reductions in allele burden, and tolerability of ruxolitinib in patients with CNL, particularly those carrying the CSF3RT618I mutation. Similar to conventional nontransplant strategies, however, no disease-modifying or survival benefits have been demonstrated. While responses to JAK-STAT inhibition in CNL have not been uniform, data are sufficient to recommend consideration of ruxolitinib in the therapeutic repertory of CNL. There remains a major unmet need for prospective trials with investigational therapies in CNL.
Collapse
|
|
12
|
B-lymphoblastic leukemia arising in a patient with chronic neutrophilic leukemia. Blood Adv 2021; 4:5389-5392. [PMID: 33147336 DOI: 10.1182/bloodadvances.2020003109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 10/07/2020] [Indexed: 12/27/2022] Open
Abstract
Key Points
We report the first identified case of chronic neutrophilic leukemia with transformation to B-lymphoblastic leukemia. Genetic alterations involving CSF3R, ASXL1, SRSF2, and RUNX1 contributed to the unusual progression and may drive B-cell leukemogenesis.
Collapse
|
|
13
|
Kuykendall AT, Tokumori FC, Komrokji RS. Traipsing Through Muddy Waters: A Critical Review of the Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) Overlap Syndromes. Hematol Oncol Clin North Am 2021; 35:337-352. [PMID: 33641873 DOI: 10.1016/j.hoc.2020.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPNs) are molecularly complex, clinically heterogeneous diseases that exhibit proliferative and dysplastic features. Diagnostic criteria use clinical, pathologic, and genomic features to distinguish between disease entities, though considerable clinical and genetic overlap persists. MDS/MPNs are associated with a poor prognosis, save for MDS/MPN with ring sideroblasts and thrombocytosis, which can behave more indolently. The current treatment approach is risk-adapted and symptom-directed and largely extrapolated from experience in MDS or MPN. Gene sequencing has demonstrated frequent mutations involving signaling, epigenetic, and splicing pathways, which present numerous therapeutic opportunities for clinical investigation.
Collapse
Affiliation(s)
- Andrew T Kuykendall
- Moffitt Cancer Center, 12902 USF Magnolia Drive, CSB 7th Floor, Tampa, FL 33612, USA.
| | - Franco Castillo Tokumori
- University of South Florida, 17 Davis Boulevard, Suite 308, Tampa, FL 33606, USA. https://twitter.com/CTFrancoMD
| | - Rami S Komrokji
- Moffitt Cancer Center, 12902 USF Magnolia Drive, CSB 7th Floor, Tampa, FL 33612, USA. https://twitter.com/Ramikomrokji
| |
Collapse
|
|
14
|
Li YP, Chen N, Ye XM, Xia YS. Eighty-year-old man with rare chronic neutrophilic leukemia caused by CSF3R T618I mutation: A case report and review of literature. World J Clin Cases 2020; 8:6337-6345. [PMID: 33392315 PMCID: PMC7760438 DOI: 10.12998/wjcc.v8.i24.6337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/02/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic neutrophilic leukemia (CNL) is a rare bone marrow proliferative tumor and a heterogeneous disorder. In 2016, the World Health Organization included activating mutations in the CSF3R gene as one of the diagnostic criteria, with CSF3R T618I being the most common mutation. The disease is often accompanied by splenomegaly, but no developmental abnormalities and significant reticular fibrosis, and no Ph chromosome and BCR-ABL fusion gene. So, it is difficult to diagnose at the first presentation in the absence of classical symptoms. Herein we describe a rare CNL patient without splenomegaly whose initial diagnostic clue was neutrophilic hyperactivity.
CASE SUMMARY The patient is an 80-year-old Han Chinese man who presented with one month of fatigue and fatigue aggravation in the last half of the month. He had no splenomegaly, but had persistent hypofibrinogenemia, obvious skin bleeding, and hemoptysis, and required repeated infusion of fibrinogen therapy. After many relevant laboratory examinations, histopathological examination, and sequencing analysis, the patient was finally diagnosed with CNL [CSF3R T618I positive: c.1853C>T (p.T618I) and c.2514T>A (p.C838)].
CONCLUSION The physical examination and blood test for tumor-related genes are insufficient to establish a diagnosis of CNL. Splenomegaly is not that important, but hyperplasia of interstitial neutrophil system and activating mutations in CSF3R are important clues to CNL diagnosis.
Collapse
Affiliation(s)
- Ya-Ping Li
- Department of Hematology, Chang'an Hospital, Xi'an 710000, Shaanxi Province, China
| | - Na Chen
- Department of Hematology, Chang'an Hospital, Xi'an 710000, Shaanxi Province, China
| | - Xian-Mei Ye
- Department of Hematology, Chang'an Hospital, Xi'an 710000, Shaanxi Province, China
| | - Yong-Shou Xia
- Department of Hematology, Chang'an Hospital, Xi'an 710000, Shaanxi Province, China
| |
Collapse
|
|
15
|
Ikeda Y, Yamanouchi J, Takenaka K. Effects of ruxolitinib on secondary myelofibrosis following chronic neutrophilic leukemia with the CSF3R T618I mutation. Ann Hematol 2020; 100:2639-2641. [PMID: 32676732 DOI: 10.1007/s00277-020-04185-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 07/13/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Yuichi Ikeda
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Jun Yamanouchi
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Katsuto Takenaka
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| |
Collapse
|
|
16
|
Szuber N, Elliott M, Tefferi A. Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management. Am J Hematol 2020; 95:212-224. [PMID: 31769070 DOI: 10.1002/ajh.25688] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 11/22/2019] [Indexed: 12/14/2022]
Abstract
DISEASE OVERVIEW Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. The seminal discovery of oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL in 2013 anchored a new scientific framework, deepening our understanding of its molecular pathogenesis, providing a diagnostic biomarker, and rationalizing the use of pharmacological targeting. DIAGNOSTIC CRITERIA In 2016, the World Health Organization (WHO) included the presence of activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 109 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN. DISEASE UPDATES Increasingly comprehensive genetic profiling of CNL has disclosed a complex genomic landscape and additional prognostically relevant mutational combinations. Though prognostic determination and therapeutic decision-making remain challenging, emerging data on prognostic markers and the use of newer therapeutic agents, such as JAK inhibitors, are helping to define state-of-the-art management in CNL.
Collapse
Affiliation(s)
- Natasha Szuber
- Department of HematologyMaisonneuve‐Rosemont Hospital Montreal Quebec Canada
| | - Michelle Elliott
- Department of Internal Medicine, Division of HematologyMayo Clinic Rochester Minnesota
| | - Ayalew Tefferi
- Department of Internal Medicine, Division of HematologyMayo Clinic Rochester Minnesota
| |
Collapse
|
|
17
|
Yin B, Chen X, Gao F, Li J, Wang HW. Analysis of gene mutation characteristics in patients with chronic neutrophilic leukaemia. ACTA ACUST UNITED AC 2019; 24:538-543. [PMID: 31315541 DOI: 10.1080/16078454.2019.1642554] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Objective: This study aims to investigate the gene mutation characteristics of chronic neutrophilic leukaemia (CNL). Method: This study retrospectively analyses the molecular biological characteristics, laboratory characteristics and clinical data of four patients with CNL that were admitted in the second Hospital of Shanxi Medical University from May 2014 to October 2016. On the basis of the molecular biological data of 22 patients with CNL and 4 patients with CNL, we further analysed the characteristics of CNL molecular mutation. Results: Two out of the four patients with CNL were carriers of colony-stimulating factor 3 receptor (CSF3R) mutation, among which two were carriers of CSF3R T618I mutation combined with ASXL1 mutation and SETBP1 mutation, and two were only carriers of JAK2 V617F mutation. According to the molecular biological data of 22 patients with CNL, 20 patients were positive for CSF3R mutation. Two patients were positive for JAK2 V617F mutation. A total of 10 patients were positive for SETBP1 mutation which was correlated with the CSF3R T618I gene mutation (P = 0.03). A total of 13 patients were positive for ASXL1 mutation. No patients carried mutations in ASXL2 and MPL genes. Conclusion and Discussion: CSF3R mutation is the main tumorigenic mutation in CNL, in which CSF3R T618I mutation is the main mutation, and an extremely small number of CNL patients may be caused by JAK2 V617F mutation. SETBP1 and ASXL1 are the most common concomitant mutations in CNL with CSF3R mutation, and SETBP1 and CSF3R T618Imutations may have a certain correlation.
Collapse
Affiliation(s)
- Bin Yin
- a Institute of Hematology , the Second Hospital of Shanxi Medical University , Taiyuan , People's Republic of China.,b Clinical Medical Laboratory Center , Children's Hospital of Shanxi , Taiyuan , People's Republic of China
| | - XiuHua Chen
- a Institute of Hematology , the Second Hospital of Shanxi Medical University , Taiyuan , People's Republic of China
| | - Feng Gao
- a Institute of Hematology , the Second Hospital of Shanxi Medical University , Taiyuan , People's Republic of China
| | - Juan Li
- a Institute of Hematology , the Second Hospital of Shanxi Medical University , Taiyuan , People's Republic of China
| | - Hong Wei Wang
- a Institute of Hematology , the Second Hospital of Shanxi Medical University , Taiyuan , People's Republic of China
| |
Collapse
|
|
18
|
Stoner RC, Press RD, Maxson JE, Tyner JW, Dao KHT. Insights on mechanisms of clonal evolution in chronic neutrophilic leukemia on ruxolitinib therapy. Leukemia 2019; 34:1684-1688. [PMID: 31844143 DOI: 10.1038/s41375-019-0688-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 11/10/2019] [Accepted: 12/05/2019] [Indexed: 11/09/2022]
Affiliation(s)
- Ryan C Stoner
- School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, mailcode KR-HEM, Portland, OR, 97239, USA
| | - Richard D Press
- Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA.,Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Julia E Maxson
- School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, mailcode KR-HEM, Portland, OR, 97239, USA.,Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Jeffrey W Tyner
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA.,Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, 97239, USA.,Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Kim-Hien T Dao
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA. .,Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, 97239, USA.
| |
Collapse
|
|
19
|
Hasserjian RP, Kelley TW, Weinberg OK, Morgan EA, Fend F. Genetic Testing in the Diagnosis and Biology of Myeloid Neoplasms (Excluding Acute Leukemias). Am J Clin Pathol 2019; 152:302-321. [PMID: 31263893 DOI: 10.1093/ajcp/aqz069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVES The 2017 Workshop of the Society for Hematopathology/European Association for Haematopathology reviewed the role of genetic testing in the diagnosis of hematopoietic neoplasms, including non-acute leukemia myeloid malignancies. METHODS The workshop panel assigned 98 submitted cases to the category of non-acute leukemia myeloid neoplasms, of which 13 were selected for oral presentation. RESULTS Data from both conventional karyotyping and genetic sequencing had important impact on diagnosis, classification, and prognostication. However, some cases had genetic results that appeared discordant from the morphology and/or clinical features. Thus, the workshop underscored the need for careful management of genetic data by the pathologist and clinician, in the context of other findings. CONCLUSIONS The workshop cases highlighted the significance of genetic aberrations in the diagnosis and treatment of non-acute leukemia myeloid neoplasms. Many genetic data have already been incorporated in the most recent World Health Organization classification, and undoubtedly they will factor increasingly in future classifications.
Collapse
Affiliation(s)
| | | | - Olga K Weinberg
- Department of Pathology, Boston Children’s Hospital, Boston, MA
| | | | - Falko Fend
- Department of Pathology and Neuropathology
- Comprehensive Cancer Care, University of Tübingen, Tübingen, Germany
| |
Collapse
|
|
20
|
Venugopal S, Mascarenhas J. Chronic Neutrophilic Leukemia: Current and Future Perspectives. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2019; 19:129-134. [DOI: 10.1016/j.clml.2018.11.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/02/2018] [Indexed: 02/02/2023]
|
|
21
|
Hu NB, Fang LW, Qin TJ, Xiao ZJ, Xu ZF. [Ruxolitinib for chronic neutrophilic leukemia: a case report and literature review]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2018; 39:1029-1032. [PMID: 30612407 PMCID: PMC7348221 DOI: 10.3760/cma.j.issn.0253-2727.2018.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Indexed: 11/05/2022]
Affiliation(s)
| | | | | | | | - Z F Xu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC, Tianjin 300020, China
| |
Collapse
|
|
22
|
Thapa B, Jamhour C, Chahine J, Rogers HJ, Daw H. Colony-stimulating Factor 3 Receptor Mutated Chronic Neutrophilic Leukemia: A Rare Case Report. Cureus 2018; 10:e3326. [PMID: 30473959 PMCID: PMC6248686 DOI: 10.7759/cureus.3326] [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: 09/06/2018] [Accepted: 09/18/2018] [Indexed: 11/30/2022] Open
Abstract
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm, which is characterized by sustained peripheral leukocytosis with neutrophilia, hepatosplenomegaly, and hypercellularity of the bone marrow, with less than 5% myeloblasts along with normal neutrophil maturation and no dysplasia. In 2016, World Health Organization (WHO) included activating mutations in the gene for colony-stimulating factor 3 receptor (CSF3R) as one of the diagnostic criteria with CSF3RT618I being the most common mutation. We report a rare case of CNL (JAK2V617F negative, BCR-ABL1 negative, CSF3RT618I positive) in an elderly female who had an aggressive clinical course of the disease.
Collapse
Affiliation(s)
- Bicky Thapa
- Internal Medicine, Cleveland Clinic - Fairview Hospital, Cleveland, USA
| | | | - Johnny Chahine
- Internal Medicine, Cleveland Clinic - Fairview Hospital, Cleveland, USA
| | - Heesun J Rogers
- Clinical Pathology, Cleveland Clinic - Fairview Hospital, Cleveland, USA
| | - Hamed Daw
- Hematology and Oncology, Cleveland Clinic - Fairview Hospital, Cleveland, USA
| |
Collapse
|
|
23
|
Elliott MA, Tefferi A. Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management. Am J Hematol 2018; 93:578-587. [PMID: 29512199 DOI: 10.1002/ajh.24983] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 11/20/2017] [Indexed: 12/21/2022]
Abstract
DISEASE OVERVIEW AND DIAGNOSIS Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥ 25 x 109 /L of which ≥ 80% are neutrophils, with < 10% circulating neutrophil precursors with blasts rarely observed. In addition, there is no dysplasia, nor clinical or molecular criteria for other myeloproliferative neoplasms. UPDATE ON DIAGNOSIS Previously the diagnosis of CNL was often as one of exclusion based on no identifiable cause for physiologic neutrophilia in patients fulfilling the aforementioned criteria. The 2016 WHO classification now recognizes somatic activating mutations of CSF3R (most commonly CSF3RT618I) as diagnostic, allowing for an accurate diagnosis for the majority of suspected cases through molecular testing. These mutations are primary driver mutations, accounting for the characteristic clinical phenotype and potential susceptibility to molecularly targeted therapy. RISK STRATIFICATION Concurrent mutations, common to myeloid neoplasms and their precursor states, most frequently in SETBP1 and ASXL1, are frequent and appear to be of prognostic significance. Although data are evolving on the full genomic profile, the rarity of CNL has delayed complete understanding of its full molecular pathogenesis and individual patient prognosis.
Collapse
Affiliation(s)
- Michelle A. Elliott
- Department of Internal Medicine, Division of Hematology; Mayo Clinic College of Medicine, 200 First St. SW; Rochester Minnesota 55905
| | - Ayalew Tefferi
- Department of Internal Medicine, Division of Hematology; Mayo Clinic College of Medicine, 200 First St. SW; Rochester Minnesota 55905
| |
Collapse
|
|
24
|
Bredeweg A, Burch M, Krause JR. Chronic neutrophilic leukemia. Proc (Bayl Univ Med Cent) 2018; 31:88-89. [PMID: 29686565 DOI: 10.1080/08998280.2017.1400300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Chronic neutrophilic leukemia is a rare myeloproliferative disorder characterized by a sustained peripheral blood neutrophilia, absence of the BCR/ABL oncoprotein, bone marrow hypercellularity with less than 5% myeloblasts and normal neutrophil maturation, and no dysplasia. This leukemia has been associated with mutations in the colony-stimulating factor 3 receptor (CSF3R) that may activate this receptor, leading to the proliferation of neutrophils that are the hallmark of chronic neutrophilic leukemia. We present a case of chronic neutrophilic leukemia and discuss the criteria for diagnosis and the significance of mutations found in this leukemia.
Collapse
Affiliation(s)
- Arthur Bredeweg
- Department of Pathology, Baylor University Medical Center at Dallas and the Charles A. Sammons Cancer Center, Dallas, Texas
| | - Micah Burch
- Department of Pathology, Baylor University Medical Center at Dallas and the Charles A. Sammons Cancer Center, Dallas, Texas
| | - John R Krause
- Department of Pathology, Baylor University Medical Center at Dallas and the Charles A. Sammons Cancer Center, Dallas, Texas
| |
Collapse
|
|
25
|
Dao KHT, Tyner JW, Gotlib J. Recent Progress in Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia. Curr Hematol Malig Rep 2018; 12:432-441. [PMID: 28983816 DOI: 10.1007/s11899-017-0413-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW We reviewed recent diagnostic and therapeutic progress in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We summarized recent genetic data that may guide future efforts towards implementing risk-adapted therapy based on mutational profile and improving disease control and survival of affected patients. RECENT FINDINGS Recent genetic data in CNL and aCML prompted modifications to the World Health Organization (WHO) diagnostic criteria, which have improved our understanding of how CNL and aCML are different diseases despite sharing common findings of peripheral granulocytosis and marrow myeloid hyperplasia. The overlap of recurrently mutated genes between aCML and CMML support considering CSF3R-T618I mutated cases as a distinct entity, either as CNL or CNL with dysplasia. Ongoing preclinical and clinical studies will help to further inform the therapeutic approach to these diseases. Our understanding of CNL and aCML has greatly advanced over the last few years. This will improve clarity for the diagnosis of these diseases, provide a strategy for risk stratification, and guide risk-adapted therapy.
Collapse
Affiliation(s)
- Kim-Hien T Dao
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, USA.
| | - Jeffrey W Tyner
- Knight Cancer Institute, Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Jason Gotlib
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
| |
Collapse
|
|
26
|
CSF3R-mutated chronic neutrophilic leukemia: long-term outcome in 19 consecutive patients and risk model for survival. Blood Cancer J 2018; 8:21. [PMID: 29449543 PMCID: PMC5814430 DOI: 10.1038/s41408-018-0058-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 01/15/2018] [Indexed: 11/13/2022] Open
|
|
27
|
Szuber N, Tefferi A. Chronic neutrophilic leukemia: new science and new diagnostic criteria. Blood Cancer J 2018; 8:19. [PMID: 29440636 PMCID: PMC5811432 DOI: 10.1038/s41408-018-0049-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 12/01/2017] [Accepted: 12/11/2017] [Indexed: 12/12/2022] Open
Abstract
Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm defined by persistent, predominantly mature neutrophil proliferation, marrow granulocyte hyperplasia, and frequent splenomegaly. The seminal discovery of oncogenic driver mutations in CSF3R in the majority of patients with CNL in 2013 generated a new scientific framework for this disease as it deepened our understanding of its molecular pathogenesis, provided a biomarker for diagnosis, and rationalized management using novel targeted therapies. Consequently, in 2016, the World Health Organization (WHO) revised the diagnostic criteria for CNL to reflect such changes in its genomic landscape, now including the presence of disease-defining activating CSF3R mutations as a key diagnostic component of CNL. In this communication, we provide a background on the history of CNL, its clinical and hemopathologic features, and its molecular anatomy, including relevant additional genetic lesions and their significance. We also outline the recently updated WHO diagnostic criteria for CNL. Further, the natural history of the disease is reviewed as well as potential prognostic variables. Finally, we summarize and discuss current treatment options as well as prospective novel therapeutic targets in hopes that they will yield meaningful improvements in patient management and outcomes.
Collapse
Affiliation(s)
- Natasha Szuber
- Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ayalew Tefferi
- Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
| |
Collapse
|
|
28
|
Langabeer SE, Haslam K, Kelly J, Quinn J, Morrell R, Conneally E. Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis. Clin Transl Oncol 2017; 20:420-423. [PMID: 28762112 DOI: 10.1007/s12094-017-1722-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 07/24/2017] [Indexed: 12/15/2022]
Abstract
PURPOSE Chronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification. MATERIALS AND METHODS A next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients. RESULTS Next-generation sequencing confirmed the CSF3R T618I in all patients with identification of concurrent SRSF2, SETBP1, NRAS and CBL mutations at diagnosis. At blast crisis, clonal evolution was evidenced by an increased CSF3R T618I allele frequency and by loss or acquisition of CBL and NRAS mutations. CONCLUSION The diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.
Collapse
Affiliation(s)
- S E Langabeer
- Central Pathology Laboratory, Cancer Molecular Diagnostics, St. James's Hospital, Dublin 8, Ireland.
| | - K Haslam
- Central Pathology Laboratory, Cancer Molecular Diagnostics, St. James's Hospital, Dublin 8, Ireland
| | - J Kelly
- Department of Clinical Genetics, Our Lady's Children's Hospital, Dublin, Ireland
| | - J Quinn
- Department of Haematology, Beaumont Hospital, Dublin, Ireland
| | - R Morrell
- Department of Haematology, Letterkenny University Hospital, Letterkenny, Ireland
| | - E Conneally
- Department of Haematology, St. James's Hospital, Dublin, Ireland
| |
Collapse
|
|
29
|
Abstract
Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are aggressive myeloid malignancies recognized as a distinct category owing to their unique combination of dysplastic and proliferative features. Although current classification schemes still emphasize morphology and exclusionary criteria, disease-defining somatic mutations and/or germline predisposition alleles are increasingly incorporated into diagnostic algorithms. The developing picture suggests that phenotypes are driven mostly by epigenetic mechanisms that reflect a complex interplay between genotype, physiological processes such as ageing and interactions between malignant haematopoietic cells and the stromal microenvironment of the bone marrow. Despite the rapid accumulation of genetic knowledge, therapies have remained nonspecific and largely inefficient. In this Review, we discuss the pathogenesis of MDS/MPN, focusing on the relationship between genotype and phenotype and the molecular underpinnings of epigenetic dysregulation. Starting with the limitations of current therapies, we also explore how the available mechanistic data may be harnessed to inform strategies to develop rational and more effective treatments, and which gaps in our knowledge need to be filled to translate biological understanding into clinical progress.
Collapse
Affiliation(s)
- Michael W N Deininger
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA
| | - Jeffrey W Tyner
- Knight Cancer Institute, Oregon Health and Science University
- Department of Cell, Developmental and Cancer Biology, Oregon Health &Science University, Portland, Oregon 97239, USA
| | - Eric Solary
- INSERM U1170, Gustave Roussy, Faculté de médecine Paris-Sud, Université Paris-Saclay, F-94805 Villejuif, France
- Department of Hematology, Gustave Roussy, F-94805 Villejuif, France
| |
Collapse
|
|
30
|
Makishima H. Somatic SETBP1 mutations in myeloid neoplasms. Int J Hematol 2017; 105:732-742. [PMID: 28447248 DOI: 10.1007/s12185-017-2241-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 04/18/2017] [Indexed: 01/06/2023]
Abstract
SETBP1 is a SET-binding protein regulating self-renewal potential through HOXA-protein activation. Somatic SETBP1 mutations were identified by whole exome sequencing in several phenotypes of myelodysplastic/myeloproliferative neoplasms (MDS/MPN), including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia as well as in secondary acute myeloid leukemia (sAML). Surprisingly, its recurrent somatic activated mutations are located at the identical positions of germline mutations reported in congenital Schinzel-Giedion syndrome. In general, somatic SETBP1 mutations have a significant clinical impact on the outcome as poor prognostic factor, due to downstream HOXA-pathway as well as associated aggressive types of chromosomal defects (-7/del(7q) and i(17q)), which is consistent with wild-type SETBP1 activation in aggressive types of acute myeloid leukemia and leukemic evolution. Biologically, mutant SETBP1 attenuates RUNX1 and activates MYB. The studies of mouse models confirmed biological significance of SETBP1 mutations in myeloid leukemogenesis, particularly associated with ASXL1 mutations. SETBP1 is a major oncogene in myeloid neoplasms, which cooperates with various genetic events and causes distinct phenotypes of MDS/MPN and sAML.
Collapse
MESH Headings
- Animals
- Carrier Proteins/genetics
- Carrier Proteins/metabolism
- Chromosome Deletion
- Chromosomes, Human, Pair 7/genetics
- Core Binding Factor Alpha 2 Subunit/genetics
- Core Binding Factor Alpha 2 Subunit/metabolism
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/metabolism
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/mortality
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/therapy
- Leukemia, Myelomonocytic, Chronic/genetics
- Leukemia, Myelomonocytic, Chronic/metabolism
- Leukemia, Myelomonocytic, Chronic/mortality
- Leukemia, Myelomonocytic, Chronic/therapy
- Leukemia, Myelomonocytic, Juvenile
- Mice
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Proto-Oncogene Proteins c-myb/genetics
- Proto-Oncogene Proteins c-myb/metabolism
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
Collapse
Affiliation(s)
- Hideki Makishima
- Department of Pathology and Tumor Biology, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
| |
Collapse
|
|
31
|
Coccaro N, Tota G, Zagaria A, Anelli L, Specchia G, Albano F. SETBP1 dysregulation in congenital disorders and myeloid neoplasms. Oncotarget 2017; 8:51920-51935. [PMID: 28881700 PMCID: PMC5584301 DOI: 10.18632/oncotarget.17231] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 03/30/2017] [Indexed: 01/19/2023] Open
Abstract
Myeloid malignancies are characterized by an extreme molecular heterogeneity, and many efforts have been made in the past decades to clarify the mechanisms underlying their pathogenesis. In this scenario SET binding protein 1 (SETBP1) has attracted a lot of interest as a new oncogene and potential marker, in addition to its involvement in the Schinzel-Giedon syndrome (SGS). Our review starts with the analysis of the structural characteristics of SETBP1, and extends to its corresponding physiological and pathological functions. Next, we describe the prevalence of SETBP1 mutations in congenital diseases and in hematologic malignancies, exploring how its alterations might contribute to tumor development and provoke clinical effects. Finally, we consider to understand how SETBP1 activation could be exploited in molecular medicine to enhance the cure rate.
Collapse
Affiliation(s)
- Nicoletta Coccaro
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Giuseppina Tota
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Antonella Zagaria
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Luisa Anelli
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Giorgina Specchia
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| | - Francesco Albano
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy
| |
Collapse
|
|
32
|
Acuna-Hidalgo R, Deriziotis P, Steehouwer M, Gilissen C, Graham SA, van Dam S, Hoover-Fong J, Telegrafi AB, Destree A, Smigiel R, Lambie LA, Kayserili H, Altunoglu U, Lapi E, Uzielli ML, Aracena M, Nur BG, Mihci E, Moreira LMA, Borges Ferreira V, Horovitz DDG, da Rocha KM, Jezela-Stanek A, Brooks AS, Reutter H, Cohen JS, Fatemi A, Smitka M, Grebe TA, Di Donato N, Deshpande C, Vandersteen A, Marques Lourenço C, Dufke A, Rossier E, Andre G, Baumer A, Spencer C, McGaughran J, Franke L, Veltman JA, De Vries BBA, Schinzel A, Fisher SE, Hoischen A, van Bon BW. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. PLoS Genet 2017; 13:e1006683. [PMID: 28346496 PMCID: PMC5386295 DOI: 10.1371/journal.pgen.1006683] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 04/10/2017] [Accepted: 03/10/2017] [Indexed: 11/18/2022] Open
Abstract
Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
Collapse
MESH Headings
- Abnormalities, Multiple/genetics
- Abnormalities, Multiple/metabolism
- Abnormalities, Multiple/pathology
- Blotting, Western
- Carrier Proteins/genetics
- Carrier Proteins/metabolism
- Cell Line
- Cell Proliferation/genetics
- Cell Transformation, Neoplastic/genetics
- Child
- Child, Preschool
- Craniofacial Abnormalities/genetics
- Craniofacial Abnormalities/metabolism
- Craniofacial Abnormalities/pathology
- Female
- Gene Expression Profiling
- Genetic Association Studies
- Genetic Predisposition to Disease/genetics
- Germ-Line Mutation
- HEK293 Cells
- Hand Deformities, Congenital/genetics
- Hand Deformities, Congenital/metabolism
- Hand Deformities, Congenital/pathology
- Hematologic Neoplasms/genetics
- Hematologic Neoplasms/metabolism
- Hematologic Neoplasms/pathology
- Humans
- Infant
- Infant, Newborn
- Intellectual Disability/genetics
- Intellectual Disability/metabolism
- Intellectual Disability/pathology
- Male
- Mutation
- Nails, Malformed/genetics
- Nails, Malformed/metabolism
- Nails, Malformed/pathology
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Phenotype
Collapse
Affiliation(s)
- Rocio Acuna-Hidalgo
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Pelagia Deriziotis
- Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
| | - Marloes Steehouwer
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Christian Gilissen
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sarah A. Graham
- Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
| | - Sipko van Dam
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
| | - Julie Hoover-Fong
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | | | - Anne Destree
- Institute of Pathology and Genetics (IPG), Gosselies, Belgium
| | - Robert Smigiel
- Department of Pediatrics and Rare Disorders, Medical University, Wroclaw, Poland
| | - Lindsday A. Lambie
- Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Hülya Kayserili
- Medical Genetics Department, Koç University School of Medicine (KUSOM), İstanbul, Turkey
| | - Umut Altunoglu
- Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey
| | - Elisabetta Lapi
- Medical Genetics Unit, Anna Meyer Children's University Hospital, Florence, Italy
| | | | - Mariana Aracena
- División de Pediatría, Pontificia Universidad Católica de Chile and Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago Chile
| | - Banu G. Nur
- Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey
| | - Ercan Mihci
- Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey
| | - Lilia M. A. Moreira
- Laboratory of Human Genetics, Biology Institute, Federal University of Bahia (UFBA), Bahia, Brazil
| | | | - Dafne D. G. Horovitz
- CERES-Genetica Reference Center and Studies in Medical Genetics and Instituto Fernandes Figueira / Fiocruz, Rio de Janeiro, Brazil
| | - Katia M. da Rocha
- Center for Human Genome Studies, Institute of Biosciences, USP, Sao Paulo, Brazil
| | | | - Alice S. Brooks
- Department of Clinical Genetics, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands
| | - Heiko Reutter
- Institute of Human Genetics, University of Bonn, Bonn, Germany and Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany
| | - Julie S. Cohen
- Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America
| | - Ali Fatemi
- Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America
| | - Martin Smitka
- Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Theresa A. Grebe
- Division of Genetics & Metabolism, Phoenix Children’s Hospital, Phoenix, Arizona, United States of America
| | | | - Charu Deshpande
- Department of Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Anthony Vandersteen
- North West Thames Regional Genetics Unit, Kennedy Galton Centre, North West London Hospitals NHS Trust, Northwick Park & St Marks Hospital, Harrow, Middlesex, United Kingdom
| | - Charles Marques Lourenço
- Neurogenetics Unit, Department of Medical Genetics School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil
| | - Andreas Dufke
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Eva Rossier
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Gwenaelle Andre
- Unité de foetopathologie, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, France
| | - Alessandra Baumer
- Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland
| | - Careni Spencer
- Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Julie McGaughran
- Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Lude Franke
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
| | - Joris A. Veltman
- Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
- Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Bert B. A. De Vries
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Albert Schinzel
- Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland
| | - Simon E. Fisher
- Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
| | - Alexander Hoischen
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
- * E-mail: (BWvB); (AH)
| | - Bregje W. van Bon
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- * E-mail: (BWvB); (AH)
| |
Collapse
|
|
33
|
Gunawan AS, McLornan DP, Wilkins B, Waghorn K, Hoade Y, Cross NCP, Harrison CN. Ruxolitinib, a potent JAK1/JAK2 inhibitor, induces temporary reductions in the allelic burden of concurrent CSF3R mutations in chronic neutrophilic leukemia. Haematologica 2017; 102:e238-e240. [PMID: 28302714 DOI: 10.3324/haematol.2017.163790] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
| | | | | | - Katherine Waghorn
- Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust and Faculty of Medicine, University of Southampton, UK
| | - Yvette Hoade
- Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust and Faculty of Medicine, University of Southampton, UK
| | - Nicholas C P Cross
- Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust and Faculty of Medicine, University of Southampton, UK
| | | |
Collapse
|
|
34
|
Cui YJ, Jiang Q, Liu JQ, Li B, Xu ZF, Qin TJ, Zhang Y, Cai WY, Zhang HL, Fang LW, Pan LJ, Hu NB, Qu SQ, Xiao ZJ. [The clinical characteristics, gene mutations and prognosis of chronic neutrophilic leukemia]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2017; 38:28-32. [PMID: 28219221 PMCID: PMC7348402 DOI: 10.3760/cma.j.issn.0253-2727.2017.01.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Indexed: 11/14/2022]
Abstract
Objective: To investigate the clinical manifestation, cytogenetics, gene mutations and prognostic factors of chronic neutrophilic leukemia (CNL) . Methods: 16 CNL cases, according to WHO (2016) -definition, were reviewed retrospectively. Identifications of the CSF3R, ASXL1, SETBP1, CALR and MPL mutations were performed by direct sequencing. JAK2 V617F mutation was detected by AS-PCR. Results: Of the 16 CNL patients, the median age was 64 (43-80) years with a male predominance of 75% (12/16) . The median hemoglobin was 114 (81-154) g/L, with median WBC of 41.20 (26.05-167.70) (10(9)/L and median PLT of 238 (91-394) ×10(9)/L.The median level of marrow fibrosis (MF) was 1 (0-3) degree. There was no other cytogenetic abnormalities except t (1;7) (p32;q11) , +21 and 14ps+ for each. All the 16 CNL patients harbored CSF3R T618I mutation. ASXL1 mutations were identified in 81% (13/16) , while SETBP1 mutations were confirmed in 63% (10/16) . The CALR K385fs*47 mutation was found. There was no mutation in JAK2 V617F or MPL in the above 16 patients. The median overall survival (OS) of patients presented with WBC≥50×10(9)/L at diagnosis (11 months) was significantly shorter than of WBC<50×10(9)/L (39 months, P=0.005) . Conclusion: CSF3R T618I mutation was specific for CNL. The median OS of CNL patients was 24 months, and WBC≥50×10(9)/L at diagnosis was an unfavorable prognostic factor.
Collapse
Affiliation(s)
- Y J Cui
- Institute of Hematology & Blood Diseases Hospital, CAMS & PUMC, The State Key Laboratory of Experimental Hematology, Tianjin 300020, China
| | | | | | | | | | | | | | | | | | | | | | | | | | - Z J Xiao
- Institute of Hematology & Blood Diseases Hospital, CAMS & PUMC, The State Key Laboratory of Experimental Hematology, Tianjin 300020, China
| |
Collapse
|
|
35
|
Abstract
Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization guidelines have been updated to include CSF3R mutations as part of the diagnostic criteria for CNL. Because of the high prevalence of CSF3R mutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion. However, recent additional genomic characterization demonstrates that CNL has much in common with other chronic myeloid malignancies at the genetic level, such as the clinically related diagnosis atypical chronic myeloid leukemia. These commonalities include mutations in SETBP1, spliceosome proteins (SRSF2, U2AF1), and epigenetic modifiers (TET2, ASXL1). Some of these same mutations also have been characterized as frequent events in clonal hematopoiesis of indeterminate potential, suggesting a more complex disease evolution than was previously understood and raising the possibility that an age-related clonal process of preleukemic cells could precede the development of CNL. The order of acquisition of CSF3R mutations relative to mutations in SETBP1, epigenetic modifiers, or the spliceosome has been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population.
Collapse
|
|
36
|
Clinical response to ruxolitinib in CSF3R T618-mutated chronic neutrophilic leukemia. Ann Hematol 2016; 95:1197-200. [PMID: 27068405 DOI: 10.1007/s00277-016-2664-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 04/04/2016] [Indexed: 11/27/2022]
|
|
37
|
Abstract
PURPOSE OF REVIEW Chronic neutrophilic leukemia (CNL) is a rare BCR-ABL1-negative myeloid malignancy that is characterized by mature granulocytosis without dysgranulopoiesis. Differential diagnosis of CNL includes reactive or secondary granulocytosis and other myeloid neoplasms, such as atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML). Herein, we focus on recently described mutations in CNL and their impact on diagnosis, prognosis and treatment. RECENT FINDINGS In 2013, membrane-proximal CSF3R mutations, most frequently CSF3RT618I, were described in CNL and aCML. Subsequent studies confirmed the presence of such mutations in nearly all patients with CNL but not in aCML. Furthermore, the majority of the patients with CSF3R-mutated CNL also expressed other mutations, such as SETBP1 and ASXL1, which might be prognostically detrimental. Laboratory studies revealed that CSF3RT618I induced JAK inhibitor-sensitive activation of JAK-STAT and CNL-like disease in mice. Case reports have indicated palliative but not disease-modifying activity of JAK inhibitor therapy in CSF3R-mutated CNL. SUMMARY CNL is now a morphologically and molecularly defined myeloid malignancy, and no longer a diagnosis of exclusion. The identification of CNL-specific molecular markers provides a much needed pathogenetic insight and also offers the opportunity to revise current diagnostic criteria and identify prognostic biomarkers and potential drug targets.
Collapse
|
|
38
|
Abstract
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that includes only 150 patients described to date meeting the latest World Health Organization (WHO) criteria and the recently reported CSF3R mutations. The diagnosis is based on morphological criteria of granulocytic cells and the exclusion of genetic drivers that are known to occur in others MPNs, such as BCR-ABL1, PDGFRA/B, or FGFR1 rearrangements. However, this scenario changed with the identification of oncogenic mutations in the CSF3R gene in approximately 83% of WHO-defined and no monoclonal gammopathy-associated CNL patients. CSF3R T618I is a highly specific molecular marker for CNL that is sensitive to inhibition in vitro and in vivo by currently approved protein kinase inhibitors. In addition to CSF3R mutations, other genetic alterations have been found, notably mutations in SETBP1, which may be used as prognostic markers to guide therapeutic decisions. These findings will help to understand the pathogenesis of CNL and greatly impact the clinical management of this disease. In this review, we discuss the new genetic alterations recently found in CNL and the clinical perspectives in its diagnosis and treatment. Fortunately, since the diagnosis of CNL is not based on exclusion anymore, the molecular characterization of the CSF3R gene must be included in the WHO criteria for CNL diagnosis.
Collapse
Affiliation(s)
- Juliane Menezes
- Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre - CNIO, Madrid, Spain
| | - Juan Cruz Cigudosa
- Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre - CNIO, Madrid, Spain
| |
Collapse
|
|
39
|
Pardanani A, Tefferi A. Is there a role for JAK inhibitors in BCR-ABL1-negative myeloproliferative neoplasms other than myelofibrosis? Leuk Lymphoma 2015; 55:2706-11. [PMID: 25520049 DOI: 10.3109/10428194.2014.985159] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Current data suggest that constitutively active JAK-STAT signaling plays a central role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasms (MPNs), regardless of the specific underlying molecular abnormality. This observation provides strong rationale for use of JAK inhibitors for MPN treatment, and these drugs were first tested in myelofibrosis (MF) patients. Ruxolitinib, a JAK-1/2 inhibitor, is effective at controlling splenomegaly and constitutional symptoms, but has limited benefit in reversing bone marrow fibrosis or inducing complete or partial remissions. Ruxolitinib is currently in Phase 3 testing for treatment of hydroxyurea resistant/intolerant polycythemia vera (PV). Preliminary data reveals response rates of 60% for hematocrit control and 38% for spleen volume reduction per protocol-defined criteria, in addition to improving disease-related symptoms. These endpoints however have limited value as surrogates for long-term clinically relevant outcomes such as freedom-from-cardiovascular/thrombohemorrhagic events or time-to-hematological transformation, and the early crossover design of the aforementioned trial introduces limitations in terms of analysis of these latter endpoints. In contrast, other recent trials in PV have demonstrated the feasibility of using long-term clinically relevant outcomes as a primary endpoint. We also discuss the role of JAK inhibitors for treatment of CSF3RT618I-mutated chronic neutrophilic leukemia and hematologic malignancies with rearranged JAK2 gene.
Collapse
|
|
40
|
Bain BJ, Ahmad S. Chronic neutrophilic leukaemia and plasma cell-related neutrophilic leukaemoid reactions. Br J Haematol 2015. [PMID: 26218186 DOI: 10.1111/bjh.13600] [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] [Indexed: 12/21/2022]
Abstract
Many cases reported as 'chronic neutrophilic leukaemia' have had an associated plasma cell neoplasm. Recent evidence suggests that the great majority of such cases represent a neutrophilic leukaemoid reaction to the underlying multiple myeloma or monoclonal gammopathy of undetermined significance. We have analysed all accessible reported cases to clarify the likely diagnosis and to ascertain whether toxic granulation, Döhle bodies and an increased neutrophil alkaline phosphatase score were useful in making a distinction between chronic neutrophilic leukaemia and a neutrophilic leukaemoid reaction. We established that all these changes occur in both conditions. Toxic granulation and Döhle bodies are more consistently present in leukaemoid reactions but also occur quite frequently in chronic neutrophilic leukaemia. The neutrophil alkaline phosphatase score is increased in both conditions and is of no value in making a distinction.
Collapse
Affiliation(s)
- Barbara J Bain
- Department of Haematology, Imperial College Healthcare NHS Trust and Centre for Haematology, St Mary's Hospital campus of Imperial College London, St Mary's Hospital, London, UK
| | - Shahzaib Ahmad
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, St Batholomew's Hospital, London, UK
| |
Collapse
|
|
41
|
Altangerel O, Cao S, Meng J, Liu P, Haiyan G, Xu Y, Zhao M. Chronic neutrophilic leukemia with overexpression of EVI-1, and concurrent CSF3R and SETBP1 mutations: A case report. Oncol Lett 2015; 10:1694-1700. [PMID: 26622734 DOI: 10.3892/ol.2015.3485] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 06/03/2015] [Indexed: 11/06/2022] Open
Abstract
Chronic neutrophilic leukemia (CNL) is a rare type of myeloproliferative neoplasm, characterized by sustained neutrophilia, splenomegaly, bone marrow granulocytic hyperplasia (without evidence of dysplasia) and an absence of the Philadelphia chromosome. Thus far, ~150 cases of CNL have been described in the literature; however, none have demonstrated overexpression of the ecotropic viral integration site-1 (EVI-1, also known as MECOM) gene. The present study describes a case that fulfilled the World Health Organization diagnostic criteria for CNL, and was associated with overexpression of EVI-1, as well as novel concurrent mutations of colony stimulating factor 3 receptor (CSF3R) and SET binding protein-1 (SETBP1). In addition, the current study briefly reviewed the relevant literature regarding novel genetic findings associated with the diagnosis and treatment of CNL. To the best of our knowledge, this is the first case report of CNL with associated EVI-1 overexpression, and concurrent CSF3R and SETBP1 mutations.
Collapse
Affiliation(s)
- Otgonbat Altangerel
- Department of Hematology, Tianjin First Central Hospital, First Central Clinical College of Tianjin Medical University, Tianjin 300192, P.R. China ; Department of Internal Medicine, Division of Hematology, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia
| | - Shannan Cao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China
| | - Juanxia Meng
- Department of Hematology, Tianjin First Central Hospital, First Central Clinical College of Tianjin Medical University, Tianjin 300192, P.R. China
| | - Peng Liu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China
| | - Gong Haiyan
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China
| | - Yuanfu Xu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China
| | - Mingfeng Zhao
- Department of Hematology, Tianjin First Central Hospital, First Central Clinical College of Tianjin Medical University, Tianjin 300192, P.R. China
| |
Collapse
|
|
42
|
Abstract
Chronic neutrophilic leukaemia (CNL) is a rare type of myeloproliferative neoplasm (MPN) characterised by sustained leucocytosis (≥25×10(9)/L) with neoplastic proliferation of neutrophilic granulocytes in blood and bone marrow. In contrast to chronic myeloid leukaemia, the disease primarily involves neutrophilic lineage with persistent proliferation of mature forms of neutrophils. No consistent cytogenetic changes have been reported. Known recurrent genetic changes in other MPNs such as JAK2, MPL, CALR, BCR-ABL1, PDGFRA, PDGFRB and FGFR1 are mostly absent. Recently, mutations in colony stimulating factor 3 receptor (CSF3R) have been reported in high frequency in CNL. This discovery has provided more insight into its pathogenesis and opened up possible treatment options. In this article, we review the clinical findings, morphology, pathobiology and differential diagnosis of CNL and treatment implications of CSF3R mutations.
Collapse
Affiliation(s)
- Guldeep Uppal
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Jerald Gong
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
43
|
Pandey R, Kapur R. Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms. Mol Cancer 2015; 14:118. [PMID: 26062813 PMCID: PMC4464249 DOI: 10.1186/s12943-015-0388-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 05/18/2015] [Indexed: 12/24/2022] Open
Abstract
Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR-ABL1 fusion + ve (Ph + ve) or -ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosine kinases in the clinic have triggered the search for kinase dependent pathways in other Ph-ve MPNs. In the past few years, identification of mutations in JAK2 associated with a majority of MPNs raised the hopes for similar success with specific targeting of JAK2. However, targeting JAK2 kinase activity has met with limited success. Subsequently, mutations in genes other than JAK2 have been identified. These mutations specifically associate with certain MPNs and can drive cytokine independent growth. Therefore, targeting alternate molecules and pathways may be more successful in management of MPNs. Among other pathways, phosphatidylinositol -3 kinase (PI3K) has emerged as a promising target as different cell surface receptor induced signaling pathways converge on the PI3K signaling axis to regulate cell metabolism, growth, proliferation, and survival. Herein, we will review the clinically relevant inhibitors of the PI3K pathway that have been evaluated or hold promise for the treatment of Ph-ve MPNs.
Collapse
Affiliation(s)
- Ruchi Pandey
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
| | - Reuben Kapur
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Department of Molecular Biology and Biochemistry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
| |
Collapse
|
|
44
|
De novo CSF3R mutation associated with transformation of myeloproliferative neoplasm to atypical CML. Ann Hematol 2015; 94:1255-6. [DOI: 10.1007/s00277-015-2366-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 03/24/2015] [Indexed: 10/23/2022]
|
|
45
|
Li B, Gale RP, Xiao Z. Molecular genetics of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia. J Hematol Oncol 2014; 7:93. [PMID: 25498990 PMCID: PMC4266232 DOI: 10.1186/s13045-014-0093-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 12/04/2014] [Indexed: 12/21/2022] Open
Abstract
According to the 2008 World Health Organization classification, chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia are rare diseases. The remarkable progress in our understanding of the molecular genetics of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms has made it clear that there are some specific genetic abnormalities in these 3 rare diseases. At the same time, there is considerable overlap among these disorders at the molecular level. The various combinations of genetic abnormalities indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. This review focuses on the current knowledge and challenges related to the molecular pathogenesis of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia and relationships between molecular findings, clinical features and prognosis.
Collapse
Affiliation(s)
| | | | - Zhijian Xiao
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
| |
Collapse
|
|
46
|
Ammatuna E, Eefting M, van Lom K, Kavelaars FF, Valk PJM, Touw IP. Atypical chronic myeloid leukemia with concomitant CSF3R T618I and SETBP1 mutations unresponsive to the JAK inhibitor ruxolitinib. Ann Hematol 2014; 94:879-80. [DOI: 10.1007/s00277-014-2272-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 12/01/2014] [Indexed: 10/24/2022]
|
|
47
|
Cui Y, Li B, Gale RP, Jiang Q, Xu Z, Qin T, Zhang P, Zhang Y, Xiao Z. CSF3R, SETBP1 and CALR mutations in chronic neutrophilic leukemia. J Hematol Oncol 2014; 7:77. [PMID: 25316523 PMCID: PMC4200198 DOI: 10.1186/s13045-014-0077-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 10/04/2014] [Indexed: 12/21/2022] Open
Abstract
The WHO 2008 definition of chronic neutrophilic leukemia (CNL) is based on clinical and laboratory parameters but not on molecular abnormalities. Mutations in CSF3R, SETBP1 and CALR are reported in patients with chronic neutrophilic leukemia (CNL). However, because CNL is rare, there are few large studies of this issue. We sequenced these genes in 14 patients who met the WHO-criteria of CNL. 8 subjects had CSF3R(T618I), 6 SETBP1 mutations and 1 a CALR mutation. Our data suggest mutation analysis of CSF3R, SETBP1 and CALR should be included in the diagnostic criteria for CNL. These data may also have therapy implications.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Zhijian Xiao
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
| |
Collapse
|