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Kreipe HH, Schlegelberger B. Cytogenetics and genomics in CML and other myeloproliferative neoplasms. Best Pract Res Clin Haematol 2024; 37:101552. [PMID: 39098796 DOI: 10.1016/j.beha.2024.101552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 04/02/2024] [Indexed: 08/06/2024]
Abstract
Chronic myeloid leukemia is defined by the presence of the Philadelphia translocation t (9; 22) resulting in the BCR::ABL1 fusion. The other myeloproliferative neoplasms (MPN) subtypes also carry typical chromosomal abnormalities, which however are not pathognomonic for a specific entity of MPN. According to the WHO classification the distinction between these entities is still based on the integration of cytological, histopathological and molecular findings. Progression of CML into accelerated and blastic phase is usually driven by additional chromosome abnormalities and ABL1 kinase mutations. In the other MPN subtypes the additional mutations besides driver gene mutations in JAK2, MPL and CALR have a decisive impact on the propensity for progression. In addition, the sequence in which the driver mutations and risk conveying additional mutations have been acquired appears to play an important role. Here, we review cytogenetic and molecular changes in CML and MPN that should be evaluated during diagnosis and disease monitoring.
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MESH Headings
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis
- Myeloproliferative Disorders/genetics
- Myeloproliferative Disorders/diagnosis
- Myeloproliferative Disorders/pathology
- Janus Kinase 2/genetics
- Mutation
- Chromosome Aberrations
- Genomics/methods
- Fusion Proteins, bcr-abl/genetics
- Receptors, Thrombopoietin/genetics
- Calreticulin/genetics
- Translocation, Genetic
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The Prognostic Role of Cytogenetics Analysis in Philadelphia Negative Myeloproliferative Neoplasms. ACTA ACUST UNITED AC 2021; 57:medicina57080813. [PMID: 34441019 PMCID: PMC8398709 DOI: 10.3390/medicina57080813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 11/16/2022]
Abstract
Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized collectively by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. Although the natural history of these neoplasms can be measured sometimes in decades more than years, the cytogenetics analysis can offer useful information regarding the prognosis. Cytogenetics has a well-established prognostic role in acute leukemias and in myelodysplastic syndromes, where it drives the clinical decisions. NGS techniques can find adverse mutations with clear prognostic value and are currently included in the prognostic evaluation of MPNs in scores such as MIPSS, GIPSS, MIPSS-PV, and MIPSS-ET. We suggest that cytogenetics (considering its availability and relative cost) has a role regarding prognostic and therapeutic decisions.
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Liu C, Zou C, Zou S, Wang Q, Xiao D, Zhang L. Abnormal hemoglobin H band in myelodysplastic syndromes (MDS): A case report. Transfus Clin Biol 2020; 28:206-210. [PMID: 33221503 DOI: 10.1016/j.tracli.2020.10.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 10/19/2020] [Accepted: 10/27/2020] [Indexed: 11/15/2022]
Abstract
Myelodysplastic syndrome (MDS) is a group of heterogeneous diseases derived from hematopoietic stem cells characterized by hemolytic anemia and high risk of conversion to acute leukemia. MDS is an age-related disease in which approximately 80% of patients are over 60years of age, male and female. Anemia is the most common clinical condition, and many patients are also associated with infection and bleeding. When the amount of α globin synthesis is insufficient, the remaining β chain forms tetramer β4, i.e. HbH. The latter forms a precipitate in red blood cells, leading to hemolytic anemia, called HbH disease, the majority of which is congenital, a small number of patients with myelodysplastic syndrome and acute myeloid leukemia may appear HbH (called acquired HbH disease). We reported a 71years old male patient diagnosed as myelodysplastic syndromes (MDS) in our hospital. The patient has a negative α-thalassemia gene test. The H band is detected by hemoglobin electrophoresis. This article analyzed and discussed this case with MDS, as well reviewed MDS.
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Affiliation(s)
- Cong Liu
- Laboratory of Ganzhou people's hospital, Ganzhou, Jiangxi 341000, China
| | - Cuicui Zou
- Laboratory of Ganzhou people's hospital, Ganzhou, Jiangxi 341000, China
| | - Shuhui Zou
- Laboratory of Ganzhou people's hospital, Ganzhou, Jiangxi 341000, China
| | - Qun Wang
- Luneng biotechnology (shenzhen) co. LTD, Shenzhen 518000, China
| | - Dejun Xiao
- Laboratory of Ganzhou people's hospital, Ganzhou, Jiangxi 341000, China
| | - Liqin Zhang
- Laboratory of Ganzhou people's hospital, Ganzhou, Jiangxi 341000, China.
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Yoon J, Yun JW, Jung CW, Kim HJ, Kim SH. Clonal dominance of a donor-derived del(20q) clone after allogeneic hematopoietic stem cell transplantation in an acute myeloid leukemia patient with del(20q). J Clin Lab Anal 2019; 33:e22951. [PMID: 31187545 PMCID: PMC6757114 DOI: 10.1002/jcla.22951] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 11/25/2022] Open
Abstract
Del(20q) is the most frequently detected large structural genetic mosaicism alteration in the healthy aging population, occurring in approximately 0.1% of older persons. Age‐related clonal hematopoiesis of copy number variations (CNVs) is linked to an increased risk of hematologic malignancies, but the clinical impact of hematopoietic stem cells (HSCs) harboring such CNVs, such as del(20q), is not clearly understood. Here, we report an acute myeloid leukemia (AML) patient with known del(20q) who acquired donor‐derived del(20q) after allogeneic hematopoietic stem cell transplantation (HSCT). The HSCs with del(20q) engrafted and expanded over time, but the patient did not clinically progress to myeloid neoplasm. Although donor‐derived del(20q) from a healthy donor has been reported previously, our case is the first to review the clonal dynamics of a del(20q) clone and its post‐transplantation impact. Since recurrent hematology neoplasm‐associated CNVs, including del(20q), may not be rare among aged HSCT donors, identifying the origin of such a CNV is necessary for clinical decisions when clonal abnormality appears after HSCT, even in recipients who previously had the same abnormality.
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Affiliation(s)
- Jung Yoon
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Won Yun
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chul Won Jung
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee-Jin Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sun-Hee Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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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.
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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
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Mosaic chromosome 20q deletions are more frequent in the aging population. Blood Adv 2017; 1:380-385. [PMID: 29296952 DOI: 10.1182/bloodadvances.2016003129] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 01/09/2017] [Indexed: 11/20/2022] Open
Abstract
Deletions on the long-arm of chromosome 20, del(20q), are common karyotypic abnormalities in myeloid disorders. Bioinformatic analyses of the B-allele frequency and log R ratio values from genome-wide association data have identified individuals who are mosaic for large structural abnormalities (>2 Mb). We investigated the most common autosomal event, namely mosaic del(20q), in 46 254 nonhematologic cancer cases and 36 229 cancer-free controls. We detected 91 mosaic del(20q) in leukocytes (80%) and buccal material (20%). The mosaic del(20q) mapped to a well-characterized minimally deleted region (MDR) reported in myeloid disorders. Common breakpoint clusters map to the coordinates of 29.9 to 31.5 Mb on the centromeric side of mosaic del(20q), and 42.0 to 45.4 Mb and 48.1 to 50.7 Mb on the telomeric end (GRCh36). Multivariate analyses suggest del(20q) increases with age, and is more common in males but less common in individuals of African ancestry. No conclusive associations were noted between the presence of mosaic del(20q) and subsequent solid tumor risk. Our observations demonstrate that the MDR of del(20q) is the most common large scale mosaic autosomal abnormality in whole blood and has a frequency of ∼1 in every 1000 adults over the age of 50, which exceeds the expected incidence of myeloid leukemia in the population. Our results indicate that subclonal mosaic events of a region implicated in myeloid disorders on 20q are more frequent than the predicted population-estimated incidence of myeloid diseases, and thus suggest that these events can be tolerated until additional events accumulate that drive myeloid disorders.
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Elliott MA, Tefferi A. Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management. Am J Hematol 2016; 91:341-9. [PMID: 26700908 DOI: 10.1002/ajh.24284] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 12/17/2015] [Indexed: 12/12/2022]
Abstract
Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥25 × 10(9) /L (of which >80% are neutrophils) and with <10 and <1% circulating immature granulocytes and blasts, respectively without dysplasia, clinical, or molecular criteria for other myeloproliferative disorders, nor an identifiable cause for physiologic neutrophilia in the absence of markers of myeloid clonality. Such a pathogenic clonal marker has now been identified as a somatic activating mutation of CSF3R, most commonly CSF3R T618I, thus demanding revision of the current WHO diagnostic classification to include the molecular criterion of mutated CSF3R. The clinical presentation, disease course and prognosis of CSF-R mutated CNL have been recently outlined. Co-operative mutations in SETBP1 and ASXL1 appear to be of prognostic significance and correlate with disease progression. Advances in the understanding of the molecular pathogenesis of CNL, have not yet fully translated into satisfactory therapeutic strategies, but the foundations for these are strengthening. Am. J. Hematol. 91:342-349, 2016. © 2015 Wiley Periodicals, Inc.
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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
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Suleiman Y, Dalia S, Liu JJ, Bowers JW, Padron E, Lancet JE, Fulp W, Moscinski LC, Komrokji RS, Zuckerman KS, Zhang L. Clinical prognostic factors and outcomes of essential thrombocythemia when transformed to myelodysplastic syndromes and acute myeloid leukemia. Leuk Res 2016; 42:52-8. [PMID: 26894965 DOI: 10.1016/j.leukres.2016.01.015] [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] [Received: 08/27/2015] [Revised: 01/14/2016] [Accepted: 01/31/2016] [Indexed: 01/31/2023]
Abstract
Transformation of essential thrombocythemia (ET) to myelodysplastic syndromes or acute myeloid leukemia is infrequent, comprising 1-5% of cases with dismal clinical outcome. Studies on prognosis in ET patients with leukemic transformation are limited. The large cohort included 40 patients (1990-2014) with ET transformation (median age of 59 years, M:F of 1:1). Median time from ET diagnosis to transformation was 76 months (26-481) with median follow-up time of 15 years. Advanced age, myelofibrosis (grade 2-3), and leukocytosis at the time of transformation were associated with inferior OS from transformation (p<0.05). Given rarity of the clinical scenario, multicenter efforts are encouraged.
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Affiliation(s)
- Yaman Suleiman
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Samir Dalia
- Mercy Clinic Oncology and Hematology Joplin, Joplin, MO, United States
| | - Jane Jijun Liu
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Jeremy W Bowers
- Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Eric Padron
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Jeffrey E Lancet
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - William Fulp
- Department of Biostatistics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Lynn C Moscinski
- Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Rami S Komrokji
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Kenneth S Zuckerman
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Ling Zhang
- Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
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Alimam S, Wilkins BS, Harrison CN. How we diagnose and treat essential thrombocythaemia. Br J Haematol 2015; 171:306-21. [DOI: 10.1111/bjh.13605] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Samah Alimam
- Department of Haematology; Guy's & St Thomas’ Hospitals NHS Foundation Trust; Guy's Hospital; London UK
| | - Bridget S. Wilkins
- Department of Cellular Pathology; Guy's & St Thomas’ Hospitals NHS Foundation Trust; St Thomas’ Hospital; London UK
| | - Claire N. Harrison
- Department of Haematology; Guy's & St Thomas’ Hospitals NHS Foundation Trust; Guy's Hospital; London UK
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Michiels JJ, Valster F, Wielenga J, Schelfout K, Raeve HD. European vs 2015-World Health Organization clinical molecular and pathological classification of myeloproliferative neoplasms. World J Hematol 2015; 4:16-53. [DOI: 10.5315/wjh.v4.i3.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 11/15/2014] [Accepted: 04/30/2015] [Indexed: 02/05/2023] Open
Abstract
The BCR/ABL fusion gene or the Ph1-chromosome in the t(9;22)(q34;q11) exerts a high tyrokinase acticity, which is the cause of chronic myeloid leukemia (CML). The 1990 Hannover Bone Marrow Classification separated CML from the myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV) and chronic megakaryocytic granulocytic myeloproliferation (CMGM). The 2006-2008 European Clinical Molecular and Pathological (ECMP) criteria discovered 3 variants of thrombocythemia: ET with features of PV (prodromal PV), “true” ET and ET associated with CMGM. The 2008 World Health Organization (WHO)-ECMP and 2014 WHO-CMP classifications defined three phenotypes of JAK2V617F mutated ET: normocellular ET (WHO-ET), hypercelluar ET due to increased erythropoiesis (prodromal PV) and ET with hypercellular megakaryocytic-granulocytic myeloproliferation. The JAK2V617F mutation load in heterozygous WHO-ET is low and associated with normal life expectance. The hetero/homozygous JAK2V617F mutation load in PV and myelofibrosis is related to myeloproliferative neoplasm (MPN) disease burden in terms of symptomatic splenomegaly, constitutional symptoms, bone marrow hypercellularity and myelofibrosis. JAK2 exon 12 mutated MPN presents as idiopathic eryhrocythemia and early stage PV. According to 2014 WHO-CMP criteria JAK2 wild type MPL515 mutated ET is the second distinct thrombocythemia featured by clustered giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow consistent with the diagnosis of “true” ET. JAK2/MPL wild type, calreticulin mutated hypercellular ET appears to be the third distinct thrombocythemia characterized by clustered larged immature dysmorphic megakaryocytes and bulky (bulbous) hyperchromatic nuclei consistent with CMGM or primary megakaryocytic granulocytic myeloproliferation.
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The molecular genetics of chronic neutrophilic leukaemia: defining a new era in diagnosis and therapy. Curr Opin Hematol 2014; 21:148-54. [PMID: 24335708 DOI: 10.1097/moh.0000000000000014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE OF REVIEW In the current WHO classification of myeloid disorders, chronic neutrophilic leukaemia (CNL) is recognized as a myeloproliferative neoplasm characterized by sustained neutrophilic leukocytosis, hepatosplenomegaly and bone marrow granulocytic hyperplasia without evidence of dysplasia, BCR-ABL1 or rearrangements of PDGFRA, PDGFRB or FGFR1. This diagnosis is contingent upon exclusion of underlying causes of reactive neutrophilia particularly if evidence of myeloid clonality is lacking. The lack of a specific molecular marker has left the diagnosis to be largely one of exclusion. Recently, the molecular landscape shifted with the discovery of specific oncogenic mutations in the colony-stimulating factor 3 receptor gene (CSF3R) in CNL patients. We review the implications for diagnosis, pathogenesis and potential for new therapeutic options. RECENT FINDINGS In 2013, oncogenic mutations in CSF3R were identified in a majority of patients with CNL and demonstrated that their downstream signalling was sensitive to known kinase inhibitors. This discovery was then validated with the demonstration of 100% CSF3R mutational frequency (predominately CSF3RT618I) in strictly WHO-defined CNL. Simultaneously, novel somatic mutations in SETBP1 were found to be enriched in CNL with possible prognostic significance. SUMMARY CNL appears to be driven by specific somatic activating CSF3R mutations. These bestow susceptibility to known kinase inhibitors, opening the door to novel specific therapeutic options for CNL. The diagnosis of CNL will no longer be one only of exclusion, and revision of the current WHO diagnostic criteria is expected to include the molecular criterion of CSF3R mutation positivity.
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Elliott MA, Tefferi A. Chronic neutrophilic leukemia 2014: Update on diagnosis, molecular genetics, and management. Am J Hematol 2014; 89:651-8. [PMID: 24845374 DOI: 10.1002/ajh.23667] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 12/28/2013] [Accepted: 01/08/2014] [Indexed: 12/21/2022]
Abstract
DISEASE OVERVIEW Chronic neutrophilic leukemia (CNL) is a myeloproliferative neoplasm characterized by sustained, mature neutrophilic leukocytosis, splenomegaly, and bone marrow granulocytic hyperplasia. DIAGNOSIS Key diagnostic criteria include leukocytosis of >25 × 10(9) /l (of which >80% are neutrophils) with <10% and <1% circulating immature granulocytes and myeloblasts, respectively. There should be no dysplasia, monocytosis, molecular evidence of BCR-ABL1, PDGFRA, PDGFRB, or FGRF1 rearrangements and no identifiable cause for physiologic neutrophilia or, if present, demonstration of myeloid clonality. DEVELOPMENTS IN MOLECULAR GENETICS: Recently, CNL has been shown to be specifically driven by somatic activating mutations of CSF3R, most commonly CSF3R T618I. As such, the diagnosis of CNL will no longer be one of exclusion only, and revision of the current WHO classification is anticipated to include the molecular criterion of mutated CSF3R.
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Affiliation(s)
- Michelle A. Elliott
- Division of Hematology, Department of Internal Medicine; Mayo Clinic College of Medicine; Rochester Minnesota
| | - Ayalew Tefferi
- Division of Hematology, Department of Internal Medicine; Mayo Clinic College of Medicine; Rochester Minnesota
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Vieira L, Vaz A, Matos P, Ambrósio AP, Nogueira M, Marques B, Pereira AM, Jordan P, da Silva MG. Three-way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation. Genes Chromosomes Cancer 2012; 51:1093-108. [PMID: 22911897 DOI: 10.1002/gcc.21994] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Accepted: 07/17/2012] [Indexed: 12/19/2022] Open
Abstract
Essential thrombocythemia (ET) is a myeloproliferative neoplasm essentially characterized by excessive production of platelets. Molecular pathogenesis of ET is linked in approximately half of the patients to intracellular cytokine signaling dysregulation as a result of thrombopoietin receptor or Janus kinase 2 (JAK2) mutations. However, genetic defects underlying cytokine transcription have not been associated with ET. Using molecular cytogenetics and whole-genome array analyses, we uncovered a submicroscopic deletion at 20q13.2 in a JAK2V617F-positive ET patient with an acquired complex chromosome translocation. The deletion encompassed the nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene that encodes a transcription factor involved in the regulation of hematopoietic cytokines. RNA interference-mediated suppression of NFATC2 mRNA or pharmacological inhibition of NFATC2 protein with 11R-VIVIT in cultured JAK2V617F-positive SET-2 megakaryocytes increased colony stimulating factor 2 (granulocyte-macrophage) (CSF2) mRNA and promoted cell proliferation. Moreover, impairment of NFATC2-calcineurin interaction with 11R-VIVIT further reduced the transcription of the NFATC2 gene. Antibody-mediated neutralization of CSF2 cytokine in inhibitor-treated cells prevented 11R-VIVIT-induced cell proliferation, indicating that impairment of NFATC2-calcineurin interaction promotes megakaryocyte proliferation through up-regulation of CSF2 transcription. Our results suggest a model in which haplo-insufficiency of NFATC2 cooperates with activation of the JAK-STAT signaling pathway in the pathogenesis of JAK2V617F-positive ET with del(20q). These results further indicate that pathogenesis of ET may be linked to genetic defects of other transcription factor genes involved in the regulation of cytokine expression.
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Affiliation(s)
- Luís Vieira
- Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal.
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14
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Kaufmann KB, Gründer A, Hadlich T, Wehrle J, Gothwal M, Bogeska R, Seeger TS, Kayser S, Pham KB, Jutzi JS, Ganzenmüller L, Steinemann D, Schlegelberger B, Wagner JM, Jung M, Will B, Steidl U, Aumann K, Werner M, Günther T, Schüle R, Rambaldi A, Pahl HL. A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2. ACTA ACUST UNITED AC 2012; 209:35-50. [PMID: 22231305 PMCID: PMC3260873 DOI: 10.1084/jem.20110540] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Mice expressing a transgene encoding the transcription factor NF-E2 in hematopoietic cells exhibit features of myeloproliferative neoplasms, including thrombocytosis, Epo-independent colony formation, stem and progenitor cell overabundance, leukocytosis, and progression to acute myeloid leukemia. The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies.
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Affiliation(s)
- Kai B Kaufmann
- Department of Experimental Anaesthesiology, Center for Clinical Research, University Hospital Freiburg, Germany
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15
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Scott LM. The JAK2 exon 12 mutations: a comprehensive review. Am J Hematol 2011; 86:668-76. [PMID: 21674578 DOI: 10.1002/ajh.22063] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Revised: 04/13/2011] [Accepted: 04/15/2011] [Indexed: 12/12/2022]
Abstract
A variety of acquired mutations targeting JAK2 exon 12 are present in those patients with the myeloproliferative neoplasm, polycythemia vera, that lack the more common JAK2V617F mutation. Both mutation types perturb erythropoiesis, with individuals presenting with a raised hematocrit, reduced serum erythropoietin levels, and erythropoietin-independent erythroid progenitor cells. However, there are also phenotypic differences that, until recently, precluded a significant proportion of patients with a JAK2 exon 12 mutation from receiving an appropriate diagnosis. Here, we review the literature published on the JAK2 exon 12 mutations and compare the biology associated with these mutations with that of JAK2V617F.
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Affiliation(s)
- Linda M Scott
- Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229, USA.
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Abstract
In the past 5 years we have witnessed significant advances in both the diagnostic process and optimal therapy for patients with essential thrombocythemia (ET). Insights into the underlying molecular mechanisms have been accompanied by the development of new diagnostic tests and by an improved understanding of the relationship between ET and other related myeloproliferative neoplasms, such as polycythemia vera and primary myelofibrosis. In the first part of this review, we describe how recent molecular and histologic studies can be integrated into a streamlined diagnostic process that is applicable to everyday clinical practice. We also address areas of current diagnostic controversy, including heterogeneity within ET and the phenotypic overlap between ET, polycythemia vera, and primary myelofibrosis. In the second part, we provide an overview of our current approach to the treatment of ET, including risk stratification, choice of cytoreductive agent, and a consideration of special situations such as the pregnant or perioperative patient. Areas of controversy discussed include the identification of those at high risk of complications and therapeutic decisions in the younger patient.
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Affiliation(s)
- Philip A Beer
- Cambridge Institute for Medical Research and Department of Haematology, University of Cambridge, Cambridge, United Kingdom
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Chaubey R, Sazawal S, Dada R, Sharma P, Pathak D, Saxena R. Trisomy 9 in a Patient with Acute Myelogenous Leukaemia FAB Type M2: A Rare Occurrence. Indian J Hematol Blood Transfus 2010; 26:103-5. [PMID: 21886394 DOI: 10.1007/s12288-010-0035-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2009] [Accepted: 02/25/2009] [Indexed: 11/25/2022] Open
Abstract
Complete trisomy 9 is a rare cytogenetic abnormality in haematological malignancies. Here we present the case history of a patient with clinical diagnosis of acute myeloblastic leukaemia (FAB type M2) and having trisomy 9 with adverse outcome.
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Hidaka T, Shide K, Shimoda H, Kameda T, Toyama K, Katayose K, Kubuki Y, Nagata K, Takenaka K, Akashi K, Okamura T, Niho Y, Mizoguchi H, Omine M, Ozawa K, Harada M, Shimoda K. The impact of cytogenetic abnormalities on the prognosis of primary myelofibrosis: a prospective survey of 202 cases in Japan. Eur J Haematol 2009; 83:328-33. [DOI: 10.1111/j.1600-0609.2009.01298.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Arikan Ş, Sen I, Bahceci M, Tuzcu A, Ayli M. An interesting case of pachydermoperiostosis with idiopathic myelofibrosis associated with monosomy 22. Int J Dermatol 2009; 48:882-5. [DOI: 10.1111/j.1365-4632.2008.03774.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Nelson ME, Steensma DP. JAK2 V617F in myeloid disorders: What do we know now, and where are we headed? Leuk Lymphoma 2009; 47:177-94. [PMID: 16321848 DOI: 10.1080/10428190500301348] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Activating tyrosine kinase (TK) mutations disrupt cellular proliferation and survival pathways and are increasingly recognized as a fundamental cause of human cancers. Until very recently, the only TK mutations widely observed in myeloid neoplasia were the BCR/ABL1 fusions characteristic of chronic myeloid leukemia and some acute leukemias, and FLT3 activating mutations in a minority of acute myeloid leukemias. Several rare TK mutations are found in various atypical myeloproliferative disorders, but big pieces of the pathobiological puzzle were glaringly missing. In the first half of 2005, one gap was filled in: 7 studies identified the same acquired amino acid substitution (V617F) in the Janus kinase 2 (JAK2) TK in large numbers of patients with diverse clonal myeloid disorders. Most affected patients suffer from the classic BCR/ABL1-negative myeloproliferative disorders (MPD), especially polycythemia vera (74% of n = 506), but a subset of people with essential thrombocythemia (36% of n = 339) or myelofibrosis with myeloid metaplasia (44% of n = 127) bear the identical mutation, as do a few individuals with myelodysplastic syndromes or an atypical myeloid disorder (7% of n = 556). This long-sought common mutation in BCR/ABL1-negative MPD raises many provocative biological and clinical questions, and demands re-evaluation of prevailing diagnostic algorithms for erythrocytosis and thrombocytosis. JAK2 V617F may provide novel molecular targets for drug therapy, and suggests other places to seek cooperating mutations or mutations associated with similar phenotypes. The story of this exciting finding will unfold rapidly in the years ahead, and ongoing developments will be important for all hematologists to understand.
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Affiliation(s)
- Maria E Nelson
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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21
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Clonal analysis of deletions on chromosome 20q and JAK2-V617F in MPD suggests that del20q acts independently and is not one of the predisposing mutations for JAK2-V617F. Blood 2009; 113:2022-7. [DOI: 10.1182/blood-2008-07-167056] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
We developed a real-time copy number polymerase chain reaction assay for deletions on chromosome 20q (del20q), screened peripheral blood granulocytes from 664 patients with myeloproliferative disorders, and identified 19 patients with del20q (2.9%), of which 14 (74%) were also positive for JAK2-V617F. To examine the temporal relationship between the occurrence of del20q and JAK2-V617F, we performed colony assays in methylcellulose, picked individual burst-forming units–erythroid (BFU-E) and colony-forming units–granulocyte (CFU-G) colonies, and genotyped each colony individually for del20q and JAK2-V617F. In 2 of 9 patients, we found that some colonies with del20q carried only wild-type JAK2, whereas other del20q colonies were JAK2-V617F positive, indicating that del20q occurred before the acquisition of JAK2-V617F. However, in colonies from 3 of 9 patients, we observed the opposite order of events. The lack of a strict temporal order of occurrence makes it doubtful that del20q represents a predisposing event for JAK2-V617F. In 2 patients with JAK2-V617F and 1 patient with MPL-W515L, microsatellite analysis revealed that del20q affected chromosomes of different parental origin and/or 9pLOH occurred at least twice. The fact that rare somatic events, such as del20q or 9pLOH, occurred more than once in subclones from the same patients suggests that the myeloproliferative disorder clone carries a predisposition to acquiring such genetic alterations.
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Crescenzi B, La Starza R, Sambani C, Parcharidou A, Pierini V, Nofrini V, Brandimarte L, Matteucci C, Aversa F, Martelli MF, Mecucci C. Totipotent stem cells bearing del(20q) maintain multipotential differentiation in Shwachman Diamond syndrome. Br J Haematol 2009; 144:116-9. [DOI: 10.1111/j.1365-2141.2008.07448.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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23
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Buxhofer-Ausch V, Gisslinger H, Berg T, Gisslinger B, Kralovics R. Acquired resistance to interferon alpha therapy associated with homozygous MPL-W515L mutation and chromosome 20q deletion in primary myelofibrosis. Eur J Haematol 2008; 82:161-3. [PMID: 19018861 DOI: 10.1111/j.1600-0609.2008.01183.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Abstract
Oncogenic mutations in JAK2 and MPL genes have recently been identified in myeloproliferative neoplasms (MPNs). In addition to these mutations, cytogenetic aberrations are frequently present at diagnosis but their role in the pathogenesis remains unclear. Two models of MPN pathogenesis have recently emerged based on either a single-hit or a multi-hit concept. The first model proposes that the acquisition of JAK2 mutations is the disease-initiating event, causing both the onset of disease phenotype and establishment of clonal hematopoiesis. The second model postulates the existence of 'pre-JAK2' mutations that establish clonal hematopoiesis before acquisition of JAK2 mutations and onset of disease phenotype. In this review, the two models have been critically evaluated in the context of the latest findings. At present, neither of the two models can be universally applied to all MPN patients due to their genetic heterogeneity. It is likely that the disease pathogenesis in some patients follows the first, and in other patients, the second model. Thus, the somatic mutations in MPN do not seem to be acquired in a predetermined order as seen in other malignancies, but occur randomly. Furthermore, the role of uniparental disomy in MPN and certain aspects of MPN therapy are discussed.
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Reilly JT. Pathogenetic insight and prognostic information from standard and molecular cytogenetic studies in the BCR-ABL-negative myeloproliferative neoplasms (MPNs). Leukemia 2008; 22:1818-27. [DOI: 10.1038/leu.2008.218] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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26
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Douet-Guilbert N, Basinko A, Morel F, Le Bris MJ, Ugo V, Morice P, Berthou C, De Braekeleer M. Chromosome 20 deletions in myelodysplastic syndromes and Philadelphia-chromosome-negative myeloproliferative disorders: characterization by molecular cytogenetics of commonly deleted and retained regions. Ann Hematol 2008; 87:537-44. [DOI: 10.1007/s00277-008-0462-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2007] [Accepted: 02/04/2008] [Indexed: 11/28/2022]
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Haferlach T, Bacher U, Kern W, Schnittger S, Haferlach C. The diagnosis of BCR/ABL-negative chronic myeloproliferative diseases (CMPD): a comprehensive approach based on morphology, cytogenetics, and molecular markers. Ann Hematol 2007; 87:1-10. [PMID: 17938925 PMCID: PMC2082654 DOI: 10.1007/s00277-007-0403-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2007] [Accepted: 09/28/2007] [Indexed: 01/27/2023]
Abstract
Recent years showed significant progress in the molecular characterization of the chronic myeloproliferative disorders (CMPD) which are classified according to the WHO classification of 2001 as polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET), CMPD/unclassifiable (CMPD-U), chronic neutrophilic leukemia, and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome, all to be delineated from BCR/ABL-positive chronic myeloid leukemia (CML). After 2001, the detection of the high frequency of the JAK2V617F mutation in PV, CIMF, and ET, and of the FIP1L1–PDGFRA fusion gene in CEL further added important information in the diagnosis of CMPD. These findings also enhanced the importance of tyrosine kinase mutations in CMPD and paved the way to a more detailed classification and to an improved definition of prognosis using also novel minimal residual disease (MRD) markers. Simultaneously, the broadening of therapeutic strategies in the CMPD, e.g., due to reduced intensity conditioning in allogeneic hematopoietic stem cell transplantation and the introduction of tyrosine kinase inhibitors in CML, in CEL, and in other ABL and PDGRFB rearrangements, increased the demands to diagnostics. Therefore, today, a multimodal diagnostic approach combining cytomorphology, cytogenetics, and individual molecular methods is needed in BCR/ABL-negative CMPD. A stringent diagnostic algorithm for characterization, choice of treatment, and monitoring of MRD will be proposed in this review.
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Affiliation(s)
- Torsten Haferlach
- MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377, Munich, Germany.
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28
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Panani AD. Cytogenetic and molecular aspects of Philadelphia negative chronic myeloproliferative disorders: clinical implications. Cancer Lett 2007; 255:12-25. [PMID: 17383090 DOI: 10.1016/j.canlet.2007.02.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2007] [Revised: 02/12/2007] [Accepted: 02/13/2007] [Indexed: 12/25/2022]
Abstract
Chronic myeloproliferative disorders (CMPD) are clonal disorders of the hematopoietic stem cell. The myeloid lineage shows increased proliferation with effective maturation, while peripheral leukocytosis, thrombocytosis or elevated red blood cell mass are found. In Philadelphia negative CMPD recurrent cytogenetic abnormalities occur, but no specific abnormality has been defined to date. The spectrum of cytogenetic aberrations is heterogeneous ranging from numerical gains and losses to structural changes including unbalanced translocations. The most common chromosomal abnormalities are 20q-, 13q-, 12p-, +8, +9, partial duplication of 1q, balanced translocations involving 8p11 and gains in 9p. Cytogenetic analysis of CMPD by conventional or molecular techniques has an important role in establishing the diagnosis of a malignant disease, adding also more information for disease outcome. Molecular studies may detect the possible role of candidate genes implicated in the neoplastic process, addressing new molecular target therapies. FIP1L1/PDGFRalpha rearrangements, as well as alterations of PDGFRbeta or FGFR1 gene have been found to be associated with specific types of CMPD. Recently, a novel somatic mutation, JAK2V617F, has been reported in most of the polycthemia vera (PV) patients, as well as in a lower percentage in essential thrombocythemia (ET) or idiopathic myelofibrosis (IMF) patients. This finding represents the most important advance in understanding of the molecular mechanisms underlined the pathogenesis of CMPD, contributing to the classification and management of patients.
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Affiliation(s)
- Anna D Panani
- Critical Care Department, Research Unit, Medical School of Athens University, Evangelismos Hospital, Ipsilandou 45-47, Athens, Greece.
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Affiliation(s)
- Peter J Campbell
- Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
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30
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Elliott MA. Chronic neutrophilic leukemia and chronic myelomonocytic leukemia: WHO defined. Best Pract Res Clin Haematol 2006; 19:571-93. [PMID: 16781489 DOI: 10.1016/j.beha.2005.07.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The World Health Organization (WHO) classification of myeloid disorders has provided updated parameters for the consistent diagnosis of two previously less than optimally defined chronic myeloid disorders, CNL and CMML. The classification of these disorders, which had been controversial, is now better defined and provides more clinically and biologically relevant disease definitions to enable uniform diagnosis and a framework to evaluate natural history and therapeutic interventions. CNL is now recognized as a distinct entity among the chronic myeloproliferative disorders and CMML is included within the new category of 'myelodysplastic/myeloproliferative diseases' (MDS/MPD). Predominant neutrophilia defines CNL whereas CMML is defined by predominant and monocytosis. In each case these defining features must be distinguished from reactive causes for the same in the absence of clear evidence of myeloid clonality (CNL and CMML) or dysplasia (CMML). The exclusion of underlying bcr/abl-driven oncogenesis is an essential component in the diagnosis of these chronic leukemic processes. The optimal therapy for both CNL and CMML remains uncertain. Current management decisions are based on small studies or extrapolated from therapeutic strategies that are effective in similar chronic, clonal myeloid disorders. Given the potential for evolution to acute leukemia or progressive refractory leucocytosis or cytopenias, allogeneic stem cell transplantation might be appropriate for younger patients. Continued reporting and investigation of specific therapeutic strategies and responses must be encouraged.
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Affiliation(s)
- Michelle A Elliott
- Department of Internal Medicine, Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
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Puigdecanet E, Espinet B, Villa O, Florensa L, Besses C, Serrano S, Solé F. Detection of abnormalities of PRV-1, TPO, and c-MPL genes detected by fluorescence in situ hybridization in essential thrombocythemia. ACTA ACUST UNITED AC 2006; 167:39-42. [PMID: 16682284 DOI: 10.1016/j.cancergencyto.2005.08.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2005] [Revised: 08/08/2005] [Accepted: 08/16/2005] [Indexed: 11/26/2022]
Abstract
No specific diagnostic markers have been described in essential thrombocythemia (ET). PRV-1 (polycythemia rubra vera-1), TPO (thrombopoietin), and c-MPL (myeloproliferative leukemia virus oncogene) genes are candidate ET molecular markers because of their implication in the pathogenesis of ET. We have studied the status of PRV-1, TPO, and c-MPL genes in 30 ET patients by a fluorescence in situ hybridization (FISH) technique using three noncommercial, locus-specific probes for PRV-1 (BAC RP11-160A19, located at 19q13.2), TPO (BAC RP11-45NP16, located at 3q27), and c-MPL (BAC RP11-297L5, located at 1p34). FISH study showed no PRV-1, TPO, and c-MPL cytogenetic abnormalities in any of the analyzed cases. Our results suggest a lack of structural and numerical rearrangements (deletions, translocations, or amplifications) of PRV-1, TPO, and c-MPL genes in ET patients.
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Affiliation(s)
- Eulàlia Puigdecanet
- Laboratori de Citogenètica i Biologia Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain.
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Marie I, Hervé F. [Mutation of protein kinase JAK2 in polycythemia vera: new perspectives in physiopathology and therapy]. Rev Med Interne 2006; 27:473-7. [PMID: 16631280 DOI: 10.1016/j.revmed.2006.02.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2005] [Revised: 11/28/2005] [Accepted: 02/04/2006] [Indexed: 01/14/2023]
Abstract
INTRODUCTION The pathogenic mechanisms of polyvythemia vera (PV) still remain unknown, although there is evidence that genetic parameters may play a role in the pathogenesis of the disease. EXEGESIS In 2005, many international research groups have identified an acquired mutation in the Janus kinase (JAK2) gene of chromosome 9; the mutation is defined by a valine-to-phenylalanine substitution at amino acid position 617 (V617F) in the JAK2's pseudokinase domain. JAK2 V617F mutation has been found in as high as 65 to 97% of patients with PV. Both in vitro and in vivo functional studies have further indicated that JAK2 V617F mutation leads to dysregulation of kinase activity, explaining, in part, clinical and biochemical features of PV. CONCLUSION These data suggest that JAK2 V617F mutation may be a novel diagnostic marker of PV. Moreover, JAK2 V617F mutation finding may permit promising therapeutic approaches in patients with PV, particularly tyrosine kinase inhibitors; preliminary series have, in fact, underscored the potential efficacy of imatinib mesylate in PV.
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Affiliation(s)
- I Marie
- Département de médecine interne, CHU de Rouen-Boisguillaume, 76031 Rouen cedex, France.
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Abstract
Myeloid disorders constitute a subgroup of hematological malignancies that is separate from lymphoid disorders. The World Health Organization system for classification of tumors of the hematopoietic system divides myeloid disorders into acute myeloid leukemia and chronic myeloid disorders based on the presence or absence, respectively, of acute myeloid leukemia--defining morphological and cytogenetic features including the presence of 20% or more myeloblasts in either the bone marrow or the peripheral blood. A recently proposed semimolecular classification system for chronic myeloid disorders recognizes 3 broad categories: the myelodysplastic syndrome, classic myeloproliferative disorders (MPD), and atypical MPD. Classic MPD includes polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and chronic myeloid leukemia. Both myelodysplastic syndrome and BCR/ABL-negative classic MPD were previously discussed as part of the current ongoing symposium on hematological malignancies. The current review focuses on the diagnosis and treatment of both molecularly defined and clinicopathologically assigned categories of atypical MPD: chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, chronic neutrophilic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, idiopathic eosinophilia including hypereosinophilic syndrome, systemic mastocytosis, unclassified MPD, and eosinophilic/mast cell disorders associated with mutations of platelet-derived growth factor receptors alpha (PDGFRA) and beta (PDGFRB), FGFR1, and KIT.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Thiele J, Varus E, Kvasnicka HM, Wickenhauser C. Trisomy 8 in prefibrotic early stages of chronic idiopathic myelofibrosis: a fluorescence in situ study of bone marrow biopsies. Acta Haematol 2006; 115:97-101. [PMID: 16424657 DOI: 10.1159/000089473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2005] [Accepted: 06/20/2005] [Indexed: 12/31/2022]
Abstract
Repeatedly performed bone marrow biopsies were studied in 30 patients with chronic idiopathic myelofibrosis (CIMF) by fluorescence in situ hybridization to detect and quantify trisomy 8 anomaly during the evolution of disease. For the establishment of threshold values we used negative and positive control specimens. At least 500 cells were evaluated in each specimen and only nuclei with three distinctive signals were regarded as positive. According to the controls, 27 patients revealed false-positive signals ranging from 0 to 1.2% (0.88 +/- 1.12). On the other hand, 3 patients showed an incidence of more than 6.5% (up to 10.1%) in the initial prefibrotic as well as advanced fibro-osteosclerotic stages of CIMF. In conclusion, trisomy 8 has been demonstrated already in the prodromal stages of CIMF and therefore is not limited to classical fibro-osteosclerotic manifestations.
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Affiliation(s)
- J Thiele
- Institute of Pathology, University of Cologne, Cologne, Germany.
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Tefferi A, Dingli D, Li CY, Dewald GW. Prognostic diversity among cytogenetic abnormalities in myelofibrosis with myeloid metaplasia. Cancer 2006; 104:1656-60. [PMID: 16104040 DOI: 10.1002/cncr.21358] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Approximately 30-50% of patients with myelofibrosis with myeloid metaplasia (MMM) demonstrate detectable cytogenetic abnormalities, the prognostic value of which has not been completely defined by previous retrospective studies. The current prospective study addresses this issue in the context of currently accepted independent prognostic variables. METHODS The current study is a single institution study in which patients with MMM were accrued between January 2000 and August 2001 and followed in a prospective fashion. All study patients underwent bone marrow examination with cytogenetic studies as well as comprehensive clinical and laboratory evaluation at the time of karyotype analysis. RESULTS Among the study cohort of 81 patients (with a median age of 61 years; 54 males), the cytogenetic findings were normal in 44 patients (54%; Group 1). The remaining 37 patients (46%) demonstrated either interstitial deletions involving the long arm of chromosome 13 or 20 (9 patients; Group 2) or other abnormalities (28 patients; Group 3). All study patients were followed prospectively for a minimum of 40 months (range, 40-55 months). Survival from the time of karyotypic analysis was found to be similar between Groups 1 and 2 but was significantly worse in Group 3. Furthermore, none of the patients in Group 2 experienced leukemic transformation, whereas five patients each from the other two groups did. Multivariate analysis identified an unfavorable cytogenetic profile (Group 3), > or = 1% circulating blasts, a hemoglobin level of <10 g/dL, and constitutional symptoms as adverse prognostic features for overall survival. CONCLUSIONS Specific cytogenetic lesions in patients with MMM might carry an independent prognostic effect for both survival and the risk of leukemic transformation. Such information should assist in decision making when considering aggressive treatment approaches.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Goodwin RG, Kell WJ, Laidler P, Long CC, Whatley SD, McKinley M, Badminton MN, Burnett AK, Williams GT, Elder GH. Photosensitivity and acute liver injury in myeloproliferative disorder secondary to late-onset protoporphyria caused by deletion of a ferrochelatase gene in hematopoietic cells. Blood 2006; 107:60-2. [PMID: 16150949 DOI: 10.1182/blood-2004-12-4939] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Late-onset erythropoietic protoporphyria (EPP) is a rare complication of myelodysplastic syndrome (MDS) but has not been described in association with a myeloproliferative disorder (MPD). EPP is normally an inherited disorder characterized by photosensitivity that starts in early childhood and results from overproduction of protoporphyrin secondary to ferrochelatase (FECH) deficiency. Severe liver disease occurs in 1% to 2% of patients. Here we report that severe photosensitivity and cholestatic liver disease in a patient with a myeloproliferative disorder was caused by excess protoporphyrin production from a clone of hematopoietic cells in which one FECH allele had been deleted. Our observations suggest that the usual explanation for the association of late-onset EPP with MPD and MDS is acquired somatic mutation of one FECH allele in bone marrow and show for the first time that the consequent overproduction of protoporphyrin may be severe enough to cause acute liver damage.
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Affiliation(s)
- Richard G Goodwin
- Department of Dermatology, University Hospital of Wales, Cardiff, United Kingdom
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37
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Abstract
Significant progress in our understanding of the molecular pathogenesis of essential thrombocythemia (ET) and the other Philadelphia (Ph) chromosome-negative myeloproliferative disorders (MPDs) has recently been achieved. Unfortunately, the diagnosis of ET still relies on a set of exclusion criteria developed years ago, as recent advances have yet to be evaluated for this purpose. The clinical course of ET is characterized by an increased incidence of thrombotic and hemorrhagic complications and an inherent tendency to progress into myelofibrosis or acute myeloid leukemia (AML). There is concern about undesirable effects of cytoreductive therapy given to prevent vascular events, particularly the risk of accelerating the rate of hematologic transformation. Thus, management involves modification of reversible vascular risk factors and further stratification according to the thrombotic risk. Myelosuppressive agents are not recommended in low-risk patients, whereas controlled studies support the therapeutic value of hydroxyurea (HU) plus aspirin in high-risk cases. Anagrelide or interferon-alpha (IFN-alpha) could be considered as second-line therapy in patients refractory or intolerant of HU. IFN-alpha is preferred in pregnant women.
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Affiliation(s)
- Guido Finazzi
- Department of Hematology, Ospedali Riuniti, Largo Barozzi 1, 24128 Bergamo, Italy.
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Simpson DA, Livanos E, Heffernan TP, Kaufmann WK. Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G1 checkpoint function. J Carcinog 2005; 4:18. [PMID: 16209708 PMCID: PMC1262734 DOI: 10.1186/1477-3163-4-18] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2005] [Accepted: 10/06/2005] [Indexed: 11/23/2022] Open
Abstract
Background Secondary cultures of human fibroblasts display a finite lifespan ending at senescence. Loss of p53 function by mutation or viral oncogene expression bypasses senescence, allowing cell division to continue for an additional 10 – 20 doublings. During this time chromosomal aberrations seen in mitotic cells increase while DNA damage and decatenation checkpoint functions in G2 cells decrease. Methods To explore this complex interplay between chromosomal instability and checkpoint dysfunction, human fibroblast lines were derived that expressed HPV16E6 oncoprotein or dominant-negative alleles of p53 (A143V and H179Q) with or without the catalytic subunit of telomerase. Results Cells with normal p53 function displayed 86 – 93% G1 arrest after exposure to 1.5 Gy ionizing radiation (IR). Expression of HPV16E6 or p53-H179Q severely attenuated G1 checkpoint function (3 – 20% arrest) while p53-A143V expression induced intermediate attenuation (55 – 57% arrest) irrespective of telomerase expression. All cell lines, regardless of telomerase expression or p53 status, exhibited a normal DNA damage G2 checkpoint response following exposure to 1.5 Gy IR prior to the senescence checkpoint. As telomerase-negative cells bypassed senescence, the frequencies of chromosomal aberrations increased generally congruent with attenuation of G2 checkpoint function. Telomerase expression allowed cells with defective p53 function to grow >175 doublings without chromosomal aberrations or attenuation of G2 checkpoint function. Conclusion Thus, chromosomal instability in cells with defective p53 function appears to depend upon telomere erosion not loss of the DNA damage induced G1 checkpoint.
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Affiliation(s)
- Dennis A Simpson
- Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, NC 27599, USA
| | - Elizabeth Livanos
- Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, NC 27599, USA
| | - Timothy P Heffernan
- Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, NC 27599, USA
| | - William K Kaufmann
- Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, NC 27599, USA
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Siebolts U, Ates M, Spitz R, Thiele J, Wickenhauser C. Quantification of clonal hematopoiesis in polycythemia vera. Virchows Arch 2005; 447:947-53. [PMID: 16133363 DOI: 10.1007/s00428-005-0047-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2005] [Accepted: 07/03/2005] [Indexed: 11/29/2022]
Abstract
Polycythemia vera (PV) is believed to represent a clonal trilineage myeloaccumulative hematopoietic disorder. This study was undertaken to estimate for the first time the proportion not only of the neoplastic clone but also of clonal and residual nonneoplastic CD34(+) progenitor cells. Chromosomal abnormalities, including trisomy 8 or 9, are phenomena associated in about 20% of PV patients. Therefore, we screened peripheral blood (PB) mononuclear cells of PV patients in the chronic phase of the disease and looked for chromosomal abnormalities performing comparative genomic hybridization. Two of the ten patients revealed cytogenetic changes, including trisomy 8 or 9. To quantify the proportion of cytogenetic abnormal cells in these patients, we applied fluorescence in situ hybridization (FISH) technique on immunomagnetically enriched cell fractions. Ninety percent of the mononuclear cells and up to 79% of PB-derived CD34(+) progenitor cells presented three signals for chromosome 8 or 9. The diagnostic value of FISH to detect trisomies in trephine biopsies was then tested in all patients under study. Although the probability to detect FISH signals in a certain section plane is reduced, constantly 10-15% of the cells revealed three signals. Concerning the CD34(+) progenitor cell pool, a distinct nonclonal population exists in these patients. Our data underline the stem cell character of PV and additionally quantify the proportion of clonal CD34(+) progenitor cells for the first time. The finding of a distinct, not aberrant, CD34(+) progenitor cell population in chronic phase PV may offer perspectives in treatment of the disease. Finally, FISH analysis of bone marrow biopsies can be helpful to consolidate diagnosis of early PV.
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Affiliation(s)
- Udo Siebolts
- Institute of Pathology, University of Cologne, Joseph-Stelzmannstr. 9, 50924 Cologne, Germany
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Brezinová J, Zemanová Z, Ransdorfová S, Sindelárová L, Sisková M, Neuwirtová R, Cermák J, Michalová K. Prognostic significance of del(20q) in patients with hematological malignancies. ACTA ACUST UNITED AC 2005; 160:188-92. [PMID: 15993278 DOI: 10.1016/j.cancergencyto.2004.12.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2004] [Revised: 12/29/2004] [Accepted: 12/30/2004] [Indexed: 11/17/2022]
Abstract
Deletions of the long arm of chromosome 20 represent a common chromosomal abnormality associated with myeloid malignancies, in particular with myeloproliferative disorders (MPD), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Using G-banding cytogenetic techniques, we found clones with del(20q) in 36 patients with hematological malignancies examined in our laboratory during the years 2001-2003: in 23 patients as a sole cytogenetic aberration and in 13 patients together with other chromosomal changes. Fluorescence in situ hybridization (FISH) with a probe specific for the 20q12 region was used in all cases to confirm the presence of the clone with deletion. For patients with additional or complex chromosomal rearrangements, multicolor FISH (M-FISH) analysis was performed. Statistical evaluation of the prognostic impact of sex, age, diagnosis, and karyotype was performed. The survival time correlated with the type of chromosomal aberration; no significant differences in survival were found for sex, age, and diagnosis.
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Affiliation(s)
- Jana Brezinová
- Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague 2, Czech Republic.
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Bacher U, Haferlach T, Schoch C. Gain of 9p due to an unbalanced rearrangement der(9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. ACTA ACUST UNITED AC 2005; 160:179-83. [PMID: 15993276 DOI: 10.1016/j.cancergencyto.2004.12.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2004] [Revised: 12/20/2004] [Accepted: 12/21/2004] [Indexed: 11/27/2022]
Abstract
Clonal aberrations leading to gain of 9p--mostly due to trisomy 9--are often reported in polycythemia vera. We report on four cases of chronic myeloproliferative disorders that demonstrated a new recurrent unbalanced rearrangement between chromosomes 9 and 18 leading to trisomy of 9p and a monosomy of 18p. This abnormality was confirmed with fluorescence in situ hybridization using chromosome painting and locus-specific probes. Three cases were diagnosed as polycythemia vera; one case presented with secondary acute myeloid leukemia following idiopathic osteomyelofibrosis. The prognostic impact of this unbalanced aberration and of gains of 9p in chronic myeloproliferative disorders remains to be clarified.
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Affiliation(s)
- Ulrike Bacher
- Department for Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 15, D-81377 Munich, Germany.
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Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, Zhao ZJ. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005; 280:22788-92. [PMID: 15863514 PMCID: PMC1201515 DOI: 10.1074/jbc.c500138200] [Citation(s) in RCA: 470] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Polycythemia vera (PV) is a human clonal hematological disorder. The molecular etiology of the disease has not been identified. PV hematopoietic progenitor cells exhibit hypersensitivity to growth factors and cytokines, suggesting possible abnormalities in protein-tyrosine kinases and phosphatases. By sequencing the entire coding regions of cDNAs of candidate enzymes, we identified a G:C--> T:A point mutation of the JAK2 tyrosine kinase in 20 of 24 PV blood samples but none in 12 normal samples. The mutation has varying degrees of heterozygosity and is apparently acquired. It changes conserved Val(617) to Phe in the pseudokinase domain of JAK2 that is known to have an inhibitory role. The mutant JAK2 has enhanced kinase activity, and when overexpressed together with the erythropoietin receptor in cells, it caused hyperactivation of erythropoietin-induced cell signaling. This gain-of-function mutation of JAK may explain the hypersensitivity of PV progenitor cells to growth factors and cytokines. Our study thus defines a molecular defect of PV.
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Affiliation(s)
- Runxiang Zhao
- Hematology/Oncology Division, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA
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Al-Assar O, Ul-Hassan A, Brown R, Wilson GA, Hammond DW, Reilly JT. Gains on 9p are common genomic aberrations in idiopathic myelofibrosis: a comparative genomic hybridization study. Br J Haematol 2005; 129:66-71. [PMID: 15801957 DOI: 10.1111/j.1365-2141.2005.05413.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Ideopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder resulting in bone marrow fibrosis as a consequence of growth factor release from clonal haematopoiesis. Conventional cytogenetic analysis identifies abnormalities in approximately a third of cases at diagnosis, although rarely uncovers unique, primary genetic events. We have used comparative genomic hybridization (CGH) to study 25 IMF cases and have compared the results with conventional cytogenetics. Metaphase cells were available for analysis in 13 cases, of which seven showed an abnormal karyotype. CGH chromosomal profiles showed imbalances in 21 of 25 cases. The most frequent aberrations were gains of 9p (12 cases), 2q (seven cases), 3p (seven cases), chromosome 4 (seven cases), 12q (seven cases), 13q (eight cases). The main losses were at 17q and occurred in six cases. The results for CGH and cytogenetics were matched for one case only. Investigation of IMF by CGH suggests that genomic aberrations are much more common than has been previously indicated by conventional cytogenetic analysis and occur in the majority of cases. Gains of 9p were the most frequent finding, occurring in 50% of patients and suggests that genes on 9p may play a crucial role in the pathogenesis of IMF.
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Affiliation(s)
- O Al-Assar
- Institute for Cancer Studies, Division of Genomic Medicine, Medical School, University of Sheffield, Sheffield, UK
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Abstract
PURPOSE OF REVIEW Diagnosis and therapy of polycythemia vera are controversial since the molecular basis of polycythemia vera remains unknown. Distinguishing between polycythemia vera and other polycythemic disorders can be very challenging. The purpose of this review is to discuss the recent progress in this area and critically review the published data in context of our knowledge of other polycythemic disorders. RECENT FINDINGS Erythropoietin is the principal regulator of regulator of erythropoiesis; its production is regulated by the degree of hypoxia. Our knowledge of cellular responses to hypoxia has recently exploded and led to the elucidation of the molecular basis of a polycythemia caused by augmentation of hypoxic sensing, Chuvash polycythemia. Similar progress in understanding the molecular basis of polycythemia vera has been elusive. A simple, readily available laboratory test to establish a diagnosis of polycythemia vera would be highly desirable; however, none exists. The value of quantization of neutrophil PRV-1 mRNA, platelet c-mpl expression, in vitro assays of erythroid progenitor cells, serum erythropoietin levels, establishing clonality in female subjects using assays employing X-chromosome-based polymorphism assays, and the progress in the chromosomal location of the gene is discussed. Integration of this information underlies the complexity of the molecular biology of polycythemia vera and indicates likely interaction of multiple genetic events in the genesis of polycythemia vera. SUMMARY The existence of family clustering of PV may facilitate the search for PV molecular basis. Only collaborative interaction of clinical researchers and laboratory scientists will lead to meaningful progress in determining the molecular basis of PV.
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Affiliation(s)
- Josef T Prchal
- Baylor College of Medicine and Michael DeBakey VAH, Houston, TX 77030, USA.
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Abstract
Clonal disorders of hematopoiesis, such as myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD), affect both hematopoietic stem cells and progenitor cells within the erythroid, platelet and granulocytic lineages and can have devastating consequences in children and adults. The genetic features of these diseases often include clonal, nonrandom chromosomal deletions (e.g., 7q-, 5q-, 20q-, 6q-, 11q- and 13q-) that appear to inactivate tumor suppressor genes required for the normal development of myeloid cells (reviewed in Bench and Fenaux). These putative tumor suppressors have proved to be much more difficult to identify than oncogenes activated by chromosomal translocations, the other major class of chromosomal lesions in MDS and MPD. Although MDS and MPD are almost certainly caused by mutations in stem/progenitor cells, the role of inactivated tumor suppressor genes in this process remains poorly understood. In a small portion of myeloid diseases, mutations have been identified in genes encoding factors known to be required for normal hematopoiesis, such as PU.1, RUNX1, CTNNA1 (alpha-catenin) and c/EBPalpha, and implicating these genes as tumor suppressors. Nonetheless, the identities of most deletion-associated tumor suppressors in these diseases remains elusive, despite complete sequencing of the human genome. The deleted regions detected by cytogenetic methods are generally very large, containing many hundreds of genes, thus making it hard to locate the critical affected gene or genes. It is also unclear whether dysfunctional myelopoiesis results from haploinsufficiency, associated with the deletion of one allele, or from homozygous inactivation due to additional point mutations or microdeletions of the retained wild-type allele. In general MDS have proved surprisingly resistant to conventional treatments. Targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, in particular the tumor suppressor genes lost through clonal, nonrandom chromosomal deletions, such as the 7q- and (del)5q.
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Affiliation(s)
- A Thomas Look
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115-6084, USA.
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Busson M, Romana S, Nguyen Khac F, Bernard O, Berger R. Cryptic translocations involving chromosome 20 in polycythemia vera. ACTA ACUST UNITED AC 2004; 47:365-71. [PMID: 15581834 DOI: 10.1016/j.anngen.2004.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Accepted: 08/26/2004] [Indexed: 11/24/2022]
Abstract
A systematic cytogenetic study was performed in 49 patients with polycythemia vera (PV) in order to investigate the occurrence of subtelomeric rearrangements of chromosome 20, the most frequently rearranged chromosome in this myeloproliferative disorder. Partial deletion of the long arm of chromosome 20 was observed in two patients and two cryptic translocations, t(1;20)(p36;q13) and t(18;20)(p11;q13) in two others, all previously treated. The localization of the breakpoints of the translocated 20 chromosomes was different in the two translocations, as shown by fluorescence in situ hybridization (FISH) to metaphase chromosomes using BAC clones. Although infrequent (2/49), cryptic translocations of chromosome 20 deserve to be detected as preliminary to identification of molecular defects in PV.
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Affiliation(s)
- Maryvonne Busson
- Inserm EMI 0210, Tour Pasteur, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris cedex 15, France
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Tenedini E, Fagioli ME, Vianelli N, Tazzari PL, Ricci F, Tagliafico E, Ricci P, Gugliotta L, Martinelli G, Tura S, Baccarani M, Ferrari S, Catani L. Gene expression profiling of normal and malignant CD34-derived megakaryocytic cells. Blood 2004; 104:3126-35. [PMID: 15271793 DOI: 10.1182/blood-2003-07-2597] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Gene expression profiles of bone marrow (BM) CD34-derived megakaryocytic cells (MKs) were compared in patients with essential thrombocythemia (ET) and healthy subjects using oligonucleotide microarray analysis to identify differentially expressed genes and disease-specific transcripts. We found that proapoptotic genes such as BAX, BNIP3, and BNIP3L were down-regulated in ET MKs together with genes that are components of the mitochondrial permeability transition pore complex, a system with a pivotal role in apoptosis. Conversely, antiapoptotic genes such as IGF1-R and CFLAR were up-regulated in the malignant cells, as was the SDF1 gene, which favors cell survival. On the basis of the array results, we characterized apoptosis of normal and ET MKs by time-course evaluation of annexin-V and sub-G1 peak DNA stainings of immature and mature MKs after culture in serum-free medium with an optimal thrombopoietin concentration, and annexin-V-positive MKs only, with decreasing thrombopoietin concentrations. ET MKs were more resistant to apoptosis than their normal counterparts. We conclude that imbalance between proliferation and apoptosis seems to be an important step in malignant ET megakaryocytopoiesis.
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Affiliation(s)
- Elena Tenedini
- Istituto di Ematologia e Oncologia Medica L. e A. Seràgnoli, Università di Bologna, Italy
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Recommandations pour la prise en charge cytogénétique des syndromes myéloprolifératifs autres que la leucémie myéloïde chronique établies par le Groupe Français de Cytogénétique Hématologique (GFCH). ACTA ACUST UNITED AC 2004; 52:241-4. [PMID: 15217703 DOI: 10.1016/j.patbio.2004.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2004] [Accepted: 04/08/2004] [Indexed: 11/24/2022]
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Zamora L, Espinet B, Florensa L, Besses C, Woessner S, Serrano S, Solé F. Is fluorescence in situ hybridization a useful method in diagnosis of polycythemia vera patients? ACTA ACUST UNITED AC 2004; 151:139-45. [PMID: 15172751 DOI: 10.1016/j.cancergencyto.2003.09.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2003] [Revised: 08/26/2003] [Accepted: 09/08/2003] [Indexed: 10/26/2022]
Abstract
Polycythemia vera (PV) is a clonal stem cell disease with trilineage myeloid involvement, characterized by a growth factor-independent erythroid proliferation. At the time of diagnosis, the percentage of cytogenetic abnormalities using conventional cytogenetic techniques is less than 20% of all PV patients. In the present study, we compare the results between conventional cytogenetic methods and fluorescence in situ hybridization (FISH) probes in 31 untreated PV patients. The karyotypes of all 31 cases were obtained from 24-hour bone marrow cell cultures. The fixed material, proceeding from conventional cytogenetics cultures, was analyzed with FISH, using centromeric probes for chromosomes 8 and 9 and locus-specific probes for 13q14 and 20q12 regions. Five cases (17.8%) showed an abnormal karyotype with conventional cytogenetics. When FISH probes were used, three alterations not detected with conventional cytogenetics, were found: two cases with D20S108 deletions and one with a D13S319 deletion, increasing the percentage of abnormal karyotypes to 19.3%. We conclude that, probably, the application of FISH with the mentioned probes, is not very useful to detect cytogenetic aberrations in untreated PV patients.
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Affiliation(s)
- Lurdes Zamora
- Laboratori de Citogenètica i Biologia Molecular, Servei de Patologia, Hospital del Mar, Passeig Marítim 25-29, Barcelona 08003, Spain.
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Prchal JT. Classification and molecular biology of polycythemias (erythrocytoses) and thrombocytosis. Hematol Oncol Clin North Am 2003; 17:1151-8, vi. [PMID: 14560779 DOI: 10.1016/s0889-8588(03)00090-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
In this article, polycythemic disorders are classified based on the current understanding of biology of erythropoieses and divided into primary and secondary polycythemias. Special emphasis is given to recently uncovered molecular bases of newly described congenital polycythemic disorders. This clarification of the pathophysiology of some of the congenital polycythemic states has obvious utility for more accurate diagnosis and rational prognostic determination. The molecular basis of congenital thrombocytoses is only beginning to be uncovered. In contrast, the molecular bases of polycythemia vera and essential thrombocythemia remain unknown, thus their diagnostic criteria are imprecise and their treatment remains largely empirical. The central premise of this article is that deciphering the molecular basis of human diseases leads to improved understanding of hematopoiesis, precise diagnosis, and the potential for development of a specific therapy.
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Affiliation(s)
- Josef T Prchal
- Section of Hematology/Oncology, Baylor College of Medicine, One Baylor Plaza, MS 525D, Houston, TX 77030, USA.
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