Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.

Tapper, William and Jones, Amy V and Kralovics, Robert and Harutyunyan, Ashot S and Zoi, Katerina and Leung, William and Godfrey, Anna L and Guglielmelli, Paola and Callaway, Alison and Ward, Daniel and Aranaz, Paula and White, Helen E and Waghorn, Katherine and Lin, Feng and Chase, Andrew and Baxter, E Joanna and Maclean, Cathy and Nangalia, Jyoti and Chen, Edwin and Evans, Paul and Short, Michael and Jack, Andrew and Wallis, Louise and Oscier, David and Duncombe, Andrew S and Schuh, Anna and Mead, Adam J and Griffiths, Michael and Ewing, Joanne and Gale, Rosemary E and Schnittger, Susanne and Haferlach, Torsten and Stegelmann, Frank and Döhner, Konstanze and Grallert, Harald and Strauch, Konstantin and Tanaka, Toshiko and Bandinelli, Stefania and Giannopoulos, Andreas and Pieri, Lisa and Mannarelli, Carmela and Gisslinger, Heinz and Barosi, Giovanni and Cazzola, Mario and Reiter, Andreas and Harrison, Claire and Campbell, Peter and Green, Anthony R and Vannucchi, Alessandro and Cross, Nicholas C P (2015) Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nature communications, 6. p. 6691. ISSN 2041-1723.

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Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.

Item Type: Article
Subjects: WH Haemic and lymphatic systems. Haematology
Divisions: Planned IP Care > Oncology and Clinical Haematology
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Depositing User: Mrs Yolande Brookes
Date Deposited: 24 Jun 2015 09:54
Last Modified: 09 Jul 2015 15:22

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