BCR-ABL1—Negative Myeloproliferative Neoplasms: A Review of Molecular Biology, Diagnosis, and Treatment

Vakil, Erik; Tefferi, Ayalew

doi:10.1016/j.clml.2011.04.002

Cited by 25 publications

(34 citation statements)

References 113 publications

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“…Recurrent point mutations, such as JAK2V617F and MPLW515L, mutations in TET2, AXL1, EZH2, SF3B1, IDH1, and IDH2 genes, uniparental disomy, and DNA copy variations are common, 1,2 so that the neoplastic process is thought to be initiated by acquired molecular lesions. However, the study of germline variants that could predispose to acquire the mutations or the disease itself, determine the phenotype, or influence the outcomes of MPNs is a growing research field in this area.…”

Section: Introductionmentioning

confidence: 99%

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

Poletto

Rosti

Villani

et al. 2012

Blood

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The frequency of A3669G single nucleotide polymorphism (SNP) of human glucocorticoid receptor has been reported increased in polycythemia vera. We investigated the frequency of A3669G SNP and its impact on disease phenotype and progression in 499 patients with primary myelofibrosis (PMF). The distribution of the A3669G allele differed between PMF patients and 2 healthy control populations (odds ratio, 1.6 and 1.8). The variant allele at the homozygous state (G/G) was associated with higher white blood cell count, larger spleen index, and higher frequency of circulating CD34 ؉ cells at diagnosis. The latter association remained significant after correction for the JAK2V617F genotype. In patients JAK2V617F mutated, the G/G genotype was associated with shorter overall survival (77.6 months vs 298 months, P ‫؍‬ .049) and blast transformation (BT)-free survival (76.7 months vs 261 months; P ‫؍‬ .018). The latter association remained significant after correction for the known BT risk factors, such as age, sex, white blood cell count, percentage of blasts, IPSS prognostic score, and homozygosity for JAK2V617F (hazard ratio ‫؍‬ 3.3; P ‫؍‬ .006). In conclusion, the glucocorticoid receptor A3669G is a susceptibility allele for PMF: it contributes to confer the phenotype of excess myeloproliferation, and it cooperates with the JAK2V617F mutation in determining BT. (Blood. 2012; 120(15):3112-3117)

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Section: Introductionmentioning

confidence: 99%

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

Poletto

Rosti

Villani

et al. 2012

Blood

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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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Hematopoietic Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms

Deeg¹

2015

Thomas’ Hematopoietic Cell Transplantation

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BCR-ABL1—Negative Myeloproliferative Neoplasms: A Review of Molecular Biology, Diagnosis, and Treatment

Cited by 25 publications

References 113 publications

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

Molecular Genetics of Myeloproliferative Disorders

Hematopoietic Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms

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