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Sex differences in the JAK2^V617F allele burden in the chronic myeloproliferative disorders

¹ Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, MD
² Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
³ Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
⁴ MD Anderson Cancer Center, Houston, TX, University of Texas, USA

Correspondence: Alison Moliterno, Division of Hematology, Johns Hopkins University School of Medicine, Ross Research Building 1025, 720 Rutland Avenue, Baltimore, MD, USA. E-mail: amoliter{at}jhmi.edu

ABSTRACT

Background: The JAK2^V617F allele burden is a variable measure, determined by the frequency of mitotic recombination events and the expansion of JAK2^V617F clones. Since variability in the JAK2^V617F allele burden is partly responsible for the distinct phenotypes seen in the myeloproliferative disorders, the objective of this study was to identify modifiers of the allele burden.

Design and Methods: Blood samples were obtained between May 2005 and January 2009 from 272 patients with essential thrombocytosis (ET), polycythemia vera (PV), and myelofibrosis (MF). The JAK2^V617F allele burden was measured by allele-specific quantitative polymerase chain reaction using DNA from purified neutrophils. Repeated measures averaged 2 years apart were available in 104 patients.

Results: Sex, age at diagnosis, and disease duration all independently influenced the JAK2^V617F allele burden. When considering all patients with myeloproliferative disorders, women had significantly lower allele burdens than men (p=0.04). In those patients with repeated measures, the increase in allele burden per year between evaluation 1 and 2 was significantly less in females compared to males. Among those that experienced disease evolution, females were 4.5 times more likely to evolve from ET to PV, but 0.23 times as likely to evolve from ET to MF.

Conclusions: Sex is an independent factor accounting for variability in the JAK2^V617F allele burden. We speculate that lower allele burdens in females suggests a lower frequency of mitotic recombination events in females compared to males, and should be considered when evaluating the relationship of allele burden to disease phenotype and also in evaluating responses to JAK2^V617F-inhibitors. Because sex may influence either genotype and/or clonal expansion as the underpinning to the variability in the JAK2^V617F allele burden, it will be important to explore factors that determine susceptibility to mitotic recombination events.

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				B. L. Stein and A. R. Moliterno Primary Myelofibrosis and the Myeloproliferative Neoplasms: The Role of Individual Variation JAMA, June 23, 2010; 303(24): 2513 - 2518. [Abstract] [Full Text] [PDF]