Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F

Sigal Gery, Qi Cao, Saskia Gueller, Hongtao Xing, Ayalew Tefferi, H. Phillip Koeffler

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)957-965
Number of pages9
JournalJournal of Leukocyte Biology
Volume85
Issue number6
DOIs
StatePublished - Jun 1 2009

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Keywords

  • Cancer
  • Cell lines
  • Protein kinases/phosphatases
  • Signaling cascade

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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