Molecular biology of Philadelphia-negative myeloproliferative neoplasms

Campregher, Paulo Vidal; Santos, Fábio Pires de Souza; Perini, Guilherme Fleury; Hamerschlak, Nelson

doi:10.5581/1516-8484.20120035

Cited by 13 publications

(15 citation statements)

References 74 publications

(89 reference statements)

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“…Although it is possible to identify one of these mutations in the majority of the BCR/ ABL-negative disorder patients, there are unidentified genetic defects in approximately 10-15% of cases, predominantly of ET and PMF and, furthermore, those mutations cannot fully explain the phenotypic heterogeneity of PN-MPNs nor the susceptibility of progression to myelofibrosis, acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS) (16). In addition, the cellular and molecular mechanisms involved in the pathophysiology of MPNs have not yet been fully clarified (16,(19)(20)(21)(22)(23)(24)(25)(26). It is well known that hematopoietic cytokine receptor signaling is largely mediated by JAKs, a family of tyrosine kinases, and their downstream transcription factors, termed signal transducer and activator of transcription (STAT).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

et al. 2017

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Abstract. Myeloproliferative neoplasms (MPNs) result from the malignant transformation of a hematopoietic stem-cell (HSC), leading to abnormal amplification and proliferation of myeloid lineages. Identification of the Janus kinase 2 (JAK2) V617F mutation developed the knowledge of Philadelphia-negative (PN)-MPNs, contributing to and influencing the definition of the phenotype and prognostic impact. Considering the lack of Portuguese epidemiological data, the present study intends to characterize the prevalence of the JAK2 mutation in a PN-MPN versus a control Portuguese population. Caucasian Portuguese PN-MPN patients (n=133) and 281 matched control subjects were investigated. No significant differences were identified between the case and control groups concerning age distribution or smoking habits. Pathology distribution was as follows: 60.2% with essential thrombocythemia (ET), 29.3% with polycythemia vera (PV) and 10.5% with primary myelofibrosis (PMF). A total of 75.0% of patients were positive for the presence of the JAK2 V617F mutation. In addition, the prevalence of PV was 87.2%, ET was 73.4% and PMF was 50.0%. The JAK2 V617F mutation is observed in various MPN phenotypes, and has an increased incidence in ET patients and a decreased incidence in PV patients. These data may contribute to improving the knowledge of the pathophysiology of these disorders, and to a more rational and efficient selection of therapeutic strategies to be adopted, notably because most of the patients are JAK2 V617F negative.

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Section: Introductionmentioning

confidence: 99%

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

et al. 2017

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“…As published in 2005 by several groups, a high percentage of patients with BCR/ABL-negative MPNs have a somatic point mutation in the JAK2 gene on 9p24 (V6174) which codes for the JAK2 kinase (Haferlach et al, 2008;Vakil and Tefferi, 2011;Campregher et al, 2010). The mutation involves a valine to a phenylalanine substitution at codon 617 (V 617) in the pseudokinase domain of the JAK2 protein ( Figure 2).…”

Section: Bcr/abl Negative Mpnsmentioning

confidence: 99%

“…The mutation interferes with the normal tyrosine kinase signalling pathway resulting in an elevated granulocyte-macrophage colony stimulating factor receptor, the erythropoietin receptor and the thrombopotien receptor (also known as MPL) (Millecker et al, 2010). The JAK2 mutation was found in 80-97% of all patients with PV, 66-50% of patients with PMF and 40-57% patients with ET (Haferlach et al, 2008;Vakil and Tefferi, 2011;Campregher et al, 2010). Several deletions in exon 12 of JAK2 have been studied.…”

Section: Bcr/abl Negative Mpnsmentioning

confidence: 99%

“…Eight distinct or separate mutations in exon Thrombocytosis less than 450 000 Â 10 9 L, often over 1000 Â 10 9 /L BCR-ABL 1 fusion gene negative 40-50% exhibit JAK2 mutation Chronic eosinophilic leukaemia, not otherwise specified (CEL/NOS) Clonal proliferation of eosinophil precursors Eosinophil count greater than 1.5 Â 10 9 L Increased eosinophils in peripheral blood, bone marrow and tissues 520% blasts in the bone marrow Mastocytosis Accumulation of mast cells in one or more organ 12 of JAK2 have been associated with haematopoietic cells to cytokine independent growth. These mutations are specific for PV and are observed predominantly with patients who are JAK2V617 negative with an overall frequency of 3% (Vakil and Tefferi, 2011;Campregher et al, 2010). The JAK2 exon 12 mutations are seen in patients with PV and not ET.…”

Section: Bcr/abl Negative Mpnsmentioning

confidence: 99%

“…This has been identified as MPLW515L. The frequency of MPLW515L is at 4% for ET and 11% for PMF, which has not been identified for PV (Vakil and Tefferi, 2011;Campregher et al, 2010;Tefferi et al, 2011).…”

Section: Bcr/abl Negative Mpnsmentioning

confidence: 99%

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Molecular Genetics of Myeloproliferative Disorders

Finnegan

2013

Encyclopedia of Life Sciences

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The myeloproliferative neoplasms (MPNs) are a group of clonal stem cell disorders characterised by increased proliferation of one or more cell lines. The 2008 World Health Organization classification of the four major MPNs includes chronic myeloid leukaemia, polycythaemia vera, primary myelofibrosis and essential thrombocythemia. In recent years, the research and utilisation of molecular markers have been paving the way for a better understanding of the MPNs for pathophysiology, classification, prognosis and treatment. With the introduction of the BCR/ABL fusion 1 gene and the JAK 2 mutation involving the tyrosine kinase pathways, it is now used in evaluating patients for diagnosis, prognosis and enhancing current practices. More and more molecular markers (MPL, TET2, LNK, CBL, IDH1 and IDH2) are being identified with the hope of having a better understanding for clinical assessment and management of these neoplasms. The importance for patient care is about understanding the role of these molecular mutations in the MPNs and what the future is for prognosis and treatment of patients diagnosed with these disorders. Key Concepts: The myeloproliferative neoplasms are clonal stem cell disorders due to unregulated cell production. The MPNs have increased tyrosine kinase involvement with an increase of cell proliferation and a loss of apoptosis. The BCR/ABL fusion gene1 plays a critical role in the pathogenesis of chronic myeloid leukaemia. The BCR/ABL fusion gene is the reciprocal translocation between the chromosomes 9 and 22. The MPNs that do not present with the BCR/ABL mutation are referred to the BCR/ABL negative neoplasms. Tyrosine kinase activation involves signal transduction in the proliferative pathways. JAK kinase is involved in myeloid cell proliferation and differentiation. JaK2 mutation results in a ‘gain of function’ for the signalling molecule of the tyrosine kinase pathway. Jak2 is present in most patients with PV, ET and PMF. MPL, LNK, TET2, CBL, ASX‐L1,IDH1/IDH2, EZH2, DNMT3 and IKZF1 are currently known mutations in BCR/ABL negative MPNs.

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The Role of Caspase Genes Polymorphisms in Genetic Susceptibility to Philadelphia-Negative Myeloproliferative Neoplasms in a Portuguese Population

Azevedo

Silva

Reichert

et al. 2018

Pathol. Oncol. Res.

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Our main aim was to evaluate the role of caspases' genes SNPs in Philadelphia-chromosome negative chronic myeloproliferative neoplasms (PN-MPNs) susceptibility. A case-control study in 133 Caucasian Portuguese PN-MPNs patients and 281 matched controls was carried out, studying SNPs in apoptosis related caspases: rs1045485 and rs1035142 (CASP8), rs1052576, rs2308950, rs1132312 and rs1052571 (CASP9), rs2227309 and rs2227310 (CASP7) and rs13006529 (CASP10). After stratification by pathology diagnosis for essential thrombocythemia (ET), female gender or JAK2 positive, there is a significant increased risk for those carrying at least one variant allele for CASP9 (C653T) polymorphism (OR 2.300 CI 95% [1.180-4.484], P = 0.014). However, when considered individually, none of the studied caspases polymorphisms was associated with PN-MPNs risk. Our results do not reveal a significant involvement of caspase genes polymorphisms on the individual susceptibility towards PN-MPNs as a whole. However, for essential thrombocythemia (ET), female gender or JAK2 positive, there is a significant increased risk to those carrying at least one variant allele for CASP9. Although larger studies are required to confirm these results and to provide conclusive evidence of association between these and other caspases variants and PN-MPNs susceptibility, these new data may contribute to a best knowledge of the pathophysiology of these disorders and, in the future, to a more rational and efficient choice of therapeutic strategies to be adopted in PN-MPNs treatment.

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Molecular biology of Philadelphia-negative myeloproliferative neoplasms

Cited by 13 publications

References 74 publications

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

Molecular Genetics of Myeloproliferative Disorders

The Role of Caspase Genes Polymorphisms in Genetic Susceptibility to Philadelphia-Negative Myeloproliferative Neoplasms in a Portuguese Population

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