Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study

Campbell, Peter J.; Scott, Linda M.; Buck, Georgina; Wheatley, Keith; East, Clare; Marsden, Joanne; Duffy, Audrey; Boyd, Elaine; Bench, Anthony J.; Scott, Mike; Vassiliou, George S.; Milligan, Donald; Smith, Steve; Erber, Wendy N.; Bareford, David; Wilkins, Bridget S.; Reilly, John T.; Harrison, Claire; Green, Anthony

doi:10.1016/s0140-6736(05)67785-9

Cited by 608 publications

(636 citation statements)

References 26 publications

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“…The role of JAK2 V617F , mutation as independent factor for thrombosis is still debated [7,[16][17][18][19][20]. In our series, we did not find any significant role of JAK2 V617F for predicting thrombosis, but some limit of our analysis should be considered because we cannot exclude that this may reflect an inadequate sample size.…”

Section: Discussionmentioning

confidence: 57%

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

et al. 2009

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International audienceThe evidence that leukocytes may contribute to the pathogenesis of thrombosis in Chronic Myeloproliferative Neoplasms is increasing but not definitive. To further enforces whether an increased leukocyte count is associated with thrombosis and whether this effect can be modulated by cytoreductive therapy, we analyzed the clinical course of 187 patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) followed at two Italian Institutions over a period of 7 years. The association was measured at diagnosis or before thrombotic events: a multivariable analysis was carried out using data at baseline and time-dependent covariates. We found that white blood cells (WBC) count above 9.5 × 10/L at diagnosis (baseline analysis) was associated with thrombosis during the follow-up (Hazard Ratio [HR] of 1.8, 0.03). At the time-dependent analysis, therapy with hydroxyurea (HU), lowering by 35% the baseline WBC level, reduced such strength of association giving a HR of 1.3 ( value non significant). We found a trend between WBC level and thrombosis in untreated low-risk patients (RR of 1.9, 95% CI 0.9 to 3.1); in high-risk patients treated with HU this correlation was clearly lost (RR 1.1, 95% CI 0.2 to 2.7). Finally, we could not identify the presence of as a risk factor for thrombosis. Properly designed prospective studies should corroborate such results

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Section: Discussionmentioning

confidence: 57%

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

et al. 2009

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“…The relationship of JAK2 V617F and erythrocytosis, the defining feature of PV, is supported by the observation of heightened erythropoietin sensitivity of homozygous V617F clones compared to heterozygous V617F clones (20), by higher hemoglobin concentrations in JAK2 V617F positive compared to JAK2 V617F-negative ET patients (21), by mouse gene transfection experiments (8) and more recently by the identification of JAK2 exon 12 lesions, which associate primarily with an erythrocytosis phenotype in both man and the mouse(10).…”

Section: Discussionmentioning

confidence: 93%

Phenotypic variations and new mutations in JAK2 V617F–negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis

Williams

Kim

Rogers

et al. 2007

Experimental Hematology

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Abstract(1) Objective-The chronic myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocytosis (ET) and idiopathic myelofibrosis (IMF), are characterized by a spectrum of clinical features and linked by common genetic lesions in JAK2 and MPL. However, the clinical phenotypes in genetically undefined MPD patients are similar to those patients with JAK2 and MPL lesions. We, therefore, sought to determine whether there were JAK2 or MPL lesions in a welldefined, JAK2 V617F-negative MPD cohort, and to determine if clinical associations could be identified based on variations identified in these genes.(2) Methods-We examined the JAK2 and MPL genes in JAK2 V617F-negative PV, IMF and idiopathic erythrocytosis (ERT) patients for sequence variations.(3) Results-We identified two previously unrecognized JAK2 mutations and three previously unrecognized MPL mutations in JAK2 V617F-negative PV, erythrocytosis and IMF patients. We identified JAK2 exon 12 lesions in 30% of JAK2 V617F-negative PV patients, and either JAK2 V617F or JAK2 exon 12 lesions in 9% of ERT patients In IMF, in addition to the MPL gene mutation, W515K, we identified three additional mutations: 204P and 2 intervening sequence transitions: IVS 11/12 and 10/11.(4) Conclusions-While the clinical phenotype of JAK2 exon 12 lesions in the MPD was predominantly erythroid, there was significant disease spectrum overlap between JAK2 V617F and JAK2 exon 12 mutations. By contrast, MPL gene mutations were not associated with erythrocytosis, but segregated primarily with the phenotypes of thrombocytosis, extramedullary disease, myelofibrosis and osteosclerosis.

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“…Subsequent studies confirmed the presence of JAK2V617F in almost all patients with PV [28,29] and in 50-60% of those with ET [30][31][32][33] or PMF [34,35]. In 2006, a somatic MPLW515L exon 10 mutation (a G to T transition at nucleotide 1544 resulting in a tryptophan to leucine substitution at codon 515 of the transmembrane region) was described in JAK2V617F-negative PMF [24].…”

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confidence: 87%

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study

Cited by 608 publications

References 26 publications

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

Phenotypic variations and new mutations in JAK2 V617F–negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

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