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

Diederik Van Bodegom, Jun Zhong, Nadja Kopp, Chaitali Dutta, Min Sik Kim, Liat Bird, Oliver Weigert, Jeffrey Tyner, Akhilesh Pandey, Akinori Yoda, David M. Weinstock

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2853-2863
Number of pages11
JournalBlood
Volume120
Issue number14
DOIs
StatePublished - Oct 4 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Van Bodegom, D., Zhong, J., Kopp, N., Dutta, C., Kim, M. S., Bird, L., Weigert, O., Tyner, J., Pandey, A., Yoda, A., & Weinstock, D. M. (2012). Differences in signaling through the B-cell leukemia oncoprotein CRLF2 in response to TSLP and through mutant JAK2. Blood, 120(14), 2853-2863. https://doi.org/10.1182/blood-2012-02-413252