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Lnk inhibits myeloproliferative disorder‐associated JAK2 mutant, JAK2V617F
Author(s) -
Gery Sigal,
Cao Qi,
Gueller Saskia,
Xing Hongtao,
Tefferi Ayalew,
Koeffler H. Phillip
Publication year - 2009
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0908575
Subject(s) - biology , mutant , myeloproliferative disorders , microbiology and biotechnology , cancer research , genetics , immunology , gene
The JAK2 mutation JAK2V617F is found frequently in patients with myeloproliferative disorders (MPD) and transforms hematopoietic cells to cytokine‐independent proliferation when expressed with specific cytokine receptors. The Src homology 2 (SH2) and pleckstrin homology (PH) domain‐containing adaptor protein Lnk (SH2B3) is a negative regulator of hematopoietic cytokine signaling. Here, we show that Lnk is a potent inhibitor of JAK2V617F constitutive activity. Lnk down‐regulates JAK2V617F‐mediated signaling and transformation in hematopoietic Ba/F3‐erythropoietin receptor cells. Furthermore, in CFU assays, Lnk‐deficient murine bone marrow cells are significantly more sensitive to transformation by JAK2V617F than wild‐type (WT) cells. Lnk, through its SH2 and PH domains, interacts with WT and mutant JAK2 and is phosphorylated by constitutively activated JAK2V617F. Finally, we found that Lnk levels are high in CD34 + hematopoietic progenitors from MPD patients and that Lnk expression is induced following JAK2 activation. Our data suggest that JAK2V617F is susceptible to endogenous negative‐feedback regulation, providing new insights into the molecular pathogenesis of MPD.