Clinical implications of the JAK2 V617F mutation in essential thrombocythemia

Antonioli, Elisabetta; Guglielmelli, Paola; Pancrazzi, Alessandro; Bogani, Costanza; Verrucci, Maria; Ponziani, Vanessa; Longo, Giovanni; Bosi, Alberto; Vannucchi, Alessandro M.

doi:10.1038/sj.leu.2403902

Cited by 224 publications

(185 citation statements)

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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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“…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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“…Some authors have reported an association between JAK2 V617F and thrombosis, 23,24 but this was not confirmed in other studies. 25,26 Different patients' selections and study designs may have played a role in these discrepancies. In our analysis, leukocytosis was more frequent in patients carrying the JAK2 mutation, but a significant role of JAK2 in predicting thrombosis was not found.…”

Section: Discussionmentioning

confidence: 99%

Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status

Carobbio

Finazzi

Guerini

et al. 2006

Blood

288

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Leukocytes contribute to the pathogenesis of thrombosis in essential thrombocythemia (ET) through recently discovered mechanisms of activation and interaction with platelets and endothelial cells. To evaluate whether an increased leukocyte count was associated with thrombosis and whether this effect can be modulated by therapy, we analyzed the clinical course of 439 patients with ET followed at the Ospedali Riuniti di Bergamo. The strength of the association was measured at diagnosis or before thrombotic events by multivariable analyses carried out using data at baseline as well as time-varying covariates. The results showed that (1) an increased leukocyte count at diagnosis was associated with thrombosis during follow-up ("baseline analysis," relative risk [RR] 2.3, 95% confidence interval [CI] 1.4-3.9, P ‫؍‬ .001); (2) hydroxyurea (HU) lowered leukocytosis and reduced the strength of the association between leukocytosis and thrombosis ("time-dependent analysis," RR 1.6, 95% CI 0.9-2.0, not significant [NS]); (3) the association of leukocytosis and thrombosis was more evident in untreated low-risk patients (RR 2.7, 95% CI 1.2-6.4, P ‫؍‬ .01) compared with HU-treated high-risk patients (RR 1.6, 95% CI 0.8-3.2, NS); and (4) the presence of JAK2 V617F was not identified as a risk factor for thrombosis during follow-up despite a significant association between the mutation and leukocytosis. We suggest validation of these findings in prospective clinical studies. (Blood.

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Clinical implications of the JAK2 V617F mutation in essential thrombocythemia

Cited by 224 publications

References 8 publications

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

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

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status

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