title: A new polycythaemia vera-associated SOCS3 SH2 mutant (SOCS3F136L) cannot regulate erythropoietin responses.
abstract: 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.
authors.affiliation: Centre for Infection and Immunity, Queen's University, Belfast, Northern Ireland.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Suessmuth
authors.forename: Joanne
authors.initials: J
authors.lastname: Elliott
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Percy
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Inami
authors.forename: Hila
authors.initials: H
authors.lastname: Attal
authors.forename: Claire N
authors.initials: CN
authors.lastname: Harrison
authors.forename: Koiti
authors.initials: K
authors.lastname: Inokuchi
authors.forename: Mary-Frances
authors.initials: MF
authors.lastname: McMullin
authors.forename: James A
authors.initials: JA
authors.lastname: Johnston
mesh_terms: D000328:Adult; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D004921:Erythropoietin / Q000097:blood / Q000502:physiology*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000235:genetics*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D004921:Erythropoietin; C507924:JAK2 protein, human; D053614:Janus Kinase 2