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, polycythemia vera, and myelofibrosis. The JAK2(V617F) allele burden was measured by an allele-specific quantitative polymerase chain reaction using DNA from purified neutrophils. Repeated measures, on average 2 years apart, were available for 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 the first and second evaluations was significantly less in females than in males. Among those who experienced disease evolution, females were 4.5 times more likely to have evolution from essential thrombocytosis to polycythemia vera, but 0.23 times as likely to have evolution from essential thrombocytosis to myelofibrosis. CONCLUSIONS: Sex is an independent factor accounting for variability in the JAK2(V617F) allele burden. We speculate that lower allele burdens in females reflect a lower frequency of mitotic recombination events in females than in 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 genotype and/or clonal expansion, underpinning the variability in JAK2(V617F) allele burden, it will be important to explore factors that determine susceptibility to mitotic recombination events.
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, polycythemia vera, and myelofibrosis. The JAK2(V617F) allele burden was measured by an allele-specific quantitative polymerase chain reaction using DNA from purified neutrophils. Repeated measures, on average 2 years apart, were available for 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 the first and second evaluations was significantly less in females than in males. Among those who experienced disease evolution, females were 4.5 times more likely to have evolution from essential thrombocytosis to polycythemia vera, but 0.23 times as likely to have evolution from essential thrombocytosis to myelofibrosis. CONCLUSIONS: Sex is an independent factor accounting for variability in the JAK2(V617F) allele burden. We speculate that lower allele burdens in females reflect a lower frequency of mitotic recombination events in females than in 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 genotype and/or clonal expansion, underpinning the variability in JAK2(V617F) allele burden, it will be important to explore factors that determine susceptibility to mitotic recombination events.
Authors: Alison R Moliterno; Donna M Williams; Ophelia Rogers; Mary Ann Isaacs; Jerry L Spivak Journal: Exp Hematol Date: 2008-08-23 Impact factor: 3.084
Authors: Raffaele Landolfi; Leonardo Di Gennaro; Maria Anna Nicolazzi; Igor Giarretta; RosaMaria Marfisi; Roberto Marchioli Journal: Intern Emerg Med Date: 2011-06-10 Impact factor: 3.397
Authors: Brady L Stein; Donna M Williams; Christine O'Keefe; Ophelia Rogers; Roxann G Ingersoll; Jerry L Spivak; Amit Verma; Jarek P Maciejewski; Michael A McDevitt; Alison R Moliterno Journal: Haematologica Date: 2011-06-28 Impact factor: 9.941
Authors: Holly L Geyer; Heidi Kosiorek; Amylou C Dueck; Robyn Scherber; Stefanie Slot; Sonja Zweegman; Peter Aw Te Boekhorst; Zhenya Senyak; Harry C Schouten; Federico Sackmann; Ana Kerguelen Fuentes; Dolores Hernández-Maraver; Heike L Pahl; Martin Griesshammer; Frank Stegelmann; Konstanze Döhner; Thomas Lehmann; Karin Bonatz; Andreas Reiter; Francoise Boyer; Gabriel Etienne; Jean-Christophe Ianotto; Dana Ranta; Lydia Roy; Jean-Yves Cahn; Claire N Harrison; Deepti Radia; Pablo Muxi; Norman Maldonado; Carlos Besses; Francisco Cervantes; Peter L Johansson; Tiziano Barbui; Giovanni Barosi; Alessandro M Vannucchi; Chiara Paoli; Francesco Passamonti; Bjorn Andreasson; Maria L Ferrari; Alessandro Rambaldi; Jan Samuelsson; Keith Cannon; Gunnar Birgegard; Zhijian Xiao; Zefeng Xu; Yue Zhang; Xiujuan Sun; Junqing Xu; Jean-Jacques Kiladjian; Peihong Zhang; Robert Peter Gale; Ruben A Mesa Journal: Haematologica Date: 2016-08-18 Impact factor: 9.941
Authors: Jerry L Spivak; Michael Considine; Donna M Williams; Conover C Talbot; Ophelia Rogers; Alison R Moliterno; Chunfa Jie; Michael F Ochs Journal: N Engl J Med Date: 2014-08-28 Impact factor: 91.245