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A new polycythaemia vera‐associated SOCS3 SH2 mutant (SOCS3 F136L ) cannot regulate erythropoietin responses
Author(s) -
Suessmuth Yvonne,
Elliott Joanne,
Percy Melanie J.,
Inami Mitsuharu,
Attal Hila,
Harrison Claire N.,
Inokuchi Koiti,
McMullin MaryFrances,
Johnston James A.
Publication year - 2009
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07860.x
Subject(s) - polycythaemia , socs3 , polycythemia vera , mutation , janus kinase 2 , germline mutation , erythropoietin , mutant , erythropoietin receptor , cancer research , biology , cytokine , erythropoiesis , myeloproliferative neoplasm , medicine , endocrinology , genetics , immunology , apoptosis , stat3 , phosphorylation , myelofibrosis , gene , anemia , bone marrow
Summary Recently several different JAK2 exon12 mutations have been identified in V617F negative polycythaemia vera (PV) or idiopathic erythrocytosis (IE) patients. The patients present with erythrocytosis, ligand‐independent cell growth and low serum erythropoietin (EPO) levels. Within this group, a deletion of amino acids 542–543 (N542‐E543del) of JAK2 is most prevalent. We have previously shown that in the presence of JAK2 V617F , suppressor of cytokine signalling 3 (SOCS3) is unable to negatively regulate EPO signalling and proliferation of V617F‐expressing cells. Here we report a PV patient heterozygous for the somatic JAK2 N542‐E543del mutation and a previously unreported germline mutation within the SH2 domain of SOCS3 (F136L). Interestingly, the SOCS3 F136L mutation was detected in a Japanese myeloproliferative disorder patient cohort at double the frequency of healthy controls. Cells expressing SOCS3 F136L had markedly elevated EPO‐induced proliferation and extended EPO‐induced JAK2 phosphorylation. Additionally, compared to wild‐type SOCS3, mutant SOCS3 had an extended half‐life in the presence of JAK2 and JAK2 N542‐E543del . Our findings suggest that this loss‐of‐function SOCS3 mutation may have contributed to disease onset by causing deregulated JAK2 signalling in the presence of a constitutively active JAK2 N542‐E543del mutant.