Blood Journal
Leading the way in experimental and clinical research in hematology

Differences in signaling through the B-cell leukemia oncoprotein CRLF2 in response to TSLP and through mutant JAK2

  1. Diederik van Bodegom1,2,
  2. Jun Zhong36,
  3. Nadja Kopp1,2,
  4. Chaitali Dutta1,2,
  5. Min-Sik Kim36,
  6. Liat Bird1,2,
  7. Oliver Weigert1,2,
  8. Jeffrey Tyner7,
  9. Akhilesh Pandey36,
  10. Akinori Yoda1,2,*, and
  11. David M. Weinstock1,2,*
  1. 1Department of Medical Oncology, Dana-Farber Cancer Institute, and
  2. 2Harvard Medical School Boston, MA;
  3. 3McKusick-Nathans Institute of Genetic Medicine, and
  4. Departments of 4Biological Chemistry,
  5. 5Oncology, and
  6. 6Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; and
  7. 7Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR

Abstract

Approximately 10% of B-cell acute lymphoblastic leukemias (B-ALLs) overexpress the cytokine receptor subunit CRLF2, which may confer a poor prognosis. CRLF2 binds its ligand thymic stromal lymphopoietin (TSLP) as a heterodimer with IL7R. Subsets of CRLF2-overexpressing B-ALLs also have a gain-of-function CRLF2 F232C mutation or activating mutations in JAK2. Whether these mutant alleles confer differences in signaling has not been addressed. Through a domain mutation analysis, we demonstrate a distinct dependence on the CRLF2 intracellular tyrosine Y368 in signaling by CRLF2 F232C, but not signaling induced by TSLP or through CRLF2/mutant JAK2. In contrast, CRLF2 signaling in each context is strictly dependent on both the CRLF2 box1 domain and the intracellular tryptophan W286. Using a global quantitative analysis of tyrosine phosphorylation induced by TSLP, we previously identified TSLP-induced phosphorylation of multiple kinases implicated in B-cell receptor signaling, including Lyn, Btk, Hck, Syk, MAPK8, MAPK9, and MAPK10. We now demonstrate that cells dependent on CRLF2/mutant JAK2 have reduced phosphorylation at these targets, suggesting that the kinases promote TSLP-mediated proliferation but serve as negative regulators of CRLF2/mutant JAK2 signaling. Thus, targetable nodes downstream of CRLF2 differ based on the presence or absence of additional mutations in CRLF2 signaling components.

  • Submitted February 23, 2012.
  • Accepted August 2, 2012.
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