SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases.
JAK2 V617F, identified in the majority of patients with myeloproliferative neoplasms, tyrosine phosphorylates SOCS3 and escapes its inhibition. Here, we demonstrate that the JAK2 exon 12 mutants described in a subset of V617F-negative MPN cases, also stabilize tyrosine phosphorylated SOCS3. SOCS3 tyrosine phosphorylation was also observed in peripheral blood mononuclear cells and granulocytes isolated from patients with JAK2 H538QK539L or JAK2 F537-K539delinsL mutations. JAK kinase inhibitors, which effectively inhibited the proliferation of cells expressing V617F or K539L, also caused a dose-dependent reduction in both mutant JAK2 and SOCS3 tyrosine phosphorylation. We propose, therefore, that SOCS3 tyrosine phosphorylation may be a novel bio-marker of myeloproliferative neoplasms resulting from a JAK2 mutation and a potential reporter of effective JAK2 inhibitor therapy currently in clinical development.
Elliott
Joanne
J
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, QUB, 2 floor, Whitla Medical Building, 97 Lisburn Rd, Belfast BT97BL, Northern Ireland.
Suessmuth
Yvonne
Y
Scott
Linda M
LM
Nahlik
Krystyna
K
McMullin
Mary Frances
MF
Constantinescu
Stefan N
SN
Green
Anthony R
AR
Johnston
James A
JA
D000818:Animals; D014408:Biomarkers, Tumor; D002460:Cell Line; D049109:Cell Proliferation; D005091:Exons; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis* / Q000235:genetics; D010766:Phosphorylation; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013601:T-Lymphocytes; D014443:Tyrosine / Q000378:metabolism
D014408:Biomarkers, Tumor; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D053614:Janus Kinase 2