Letter abstract


Nature Genetics 41, 455 - 459 (2009)
Published online: 15 March 2009 | doi:10.1038/ng.342

A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms

Outi Kilpivaara1,12, Semanti Mukherjee2,3,12, Alison M Schram1, Martha Wadleigh4, Ann Mullally4,5, Benjamin L Ebert5,6, Adam Bass4,6, Sachie Marubayashi1, Adriana Heguy1, Guillermo Garcia-Manero7, Hagop Kantarjian7, Kenneth Offit8, Richard M Stone4, D Gary Gilliland4,5,6,9,10, Robert J Klein2 & Ross L Levine1,11

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Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis1, 2, 3, 4, 5. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2V617F) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis6, 7, 8, 9, 10, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci11. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2V617F-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2V617F is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.

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  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  2. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  3. Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, New York, New York, USA.
  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  5. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  6. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  7. Department of Leukemia, M.D. Anderson Cancer Center, Houston, Texas, USA.
  8. Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  9. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
  10. Harvard Stem Cell Institute, Boston, Massachusetts, USA.
  11. Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  12. These authors contributed equally to this work.

Correspondence to: Robert J Klein2 e-mail: kleinr@mskcc.org

Correspondence to: Ross L Levine1,11 e-mail: leviner@mskcc.org