Prognostic significance of ASXL1, JAK2V617F mutations and JAK2V617F allele burden in Philadelphia-negative myeloproliferative neoplasms

Abstract

BackgroundDespite insights into the genetic basis of Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs), a significant proportion of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients present with no known MPN disease alleles. There were no previous studies investigating the impact of ASXL1 mutations in Ph-negative MPNs in Turkey. In the current study, we investigated the prognostic significance of ASXL1 mutations in Turkish MPN patients. We also aimed to determine the prognostic significance of JAK2V617F allele burden and the relationship of JAK2V617F mutation with ASXL1 mutations in Ph-negative MPNs.MethodsAbout 184 patients from a single center diagnosed with Ph-negative MPNs were screened for ASXL1, JAK2V617F mutations, and JAK2V617F allele burden: 107 ET and 77 PMF.ResultsA total of 29 ASXL1 mutations were detected in 24.7% of PMF and 8.4% of ET patients. ASXL1-mutated ET patients showed a trend toward an increase in the incidence of cerebrovascular events and higher total leukocyte counts. ASXL1-mutation in PMF was associated with older age and a higher prevalence of bleeding complications. In univariate analysis, overall survival (OS) was significantly reduced in ASXL1-mutated PMF patients. In multivariate analysis, Dynamic International Prognostic Scoring System-plus high-risk category and ASXL1 mutation status were independently associated with shorter survival in PMF. In PMF, mutational status and allele burden of JAK2V617F showed no difference in terms of OS and leukemia-free survival.ConclusionWe conclude that ASXL1 mutations are molecular predictors of short OS in PMF.

Mutation status of essential thrombocythemia and primary myelofibrosis defines clinical outcome

“…This has recently been reported for PMF, but no significant difference for survival in ET was seen. 13 In addition, mutation in SRSF2 significantly correlated to inferior OS in ET patients in the current study. Three different mutations affecting the mutational hotspot P95 were found in three ET and three PMF patients.…”

Highly variable mutational profile of ASXL1 in myelofibrosis

“…In the present study, only one mutation, not previously reported, was found in more than one patient (p.Cys594MetfsX25, found in two cases). Indeed, only 5 of the 11 mutations found in our study have been previously described (Table ) . Other studies have found similar results: of 115 mutations described in the literature , only 21 mutations have been found in more than one case and only 12 have been identified in patients from more than one series.…”

“…Although their pathogenetic role in MF remains unclear, ASXL1 mutations have been found early in the course of the disease, suggesting a possible driving role . The most common mutation in MF is p.Gly646TrpfsX12 . The objective of this study was to analyze the frequency, mutational profile and the prognostic significance of ASXL1 mutations in a series of patients with MF diagnosed in eight Spanish hospitals.…”

Assessing the thrombotic risk of patients with essential thrombocythemia in the genomic era

“…95 In another experience, ASXL1 mutations (detected in 8.4% of ET patients, and co-existent with JAK2 mutations in two- thirds of them) appeared to confer a statistically insignificant increase in the risk of arterial, but not venous thrombosis. 96 …”