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Differences in signaling through the B-cell leukemia oncoprotein CRLF2 in response to TSLP and through mutant JAK2.
van Bodegom, Diederik; Zhong, Jun; Kopp, Nadja; Dutta, Chaitali; Kim, Min-Sik; Bird, Liat; Weigert, Oliver; Tyner, Jeffrey; Pandey, Akhilesh; Yoda, Akinori; Weinstock, David M.
Afiliação
  • van Bodegom D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Blood ; 120(14): 2853-63, 2012 Oct 04.
Article em En | MEDLINE | ID: mdl-22915648
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia-Linfoma Linfoblástico de Células Precursoras B / Citocinas / Receptores de Citocinas / Janus Quinase 2 / Mutação Limite: Animals / Humans Idioma: En Revista: Blood Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia-Linfoma Linfoblástico de Células Precursoras B / Citocinas / Receptores de Citocinas / Janus Quinase 2 / Mutação Limite: Animals / Humans Idioma: En Revista: Blood Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos