Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia.
Blood
; 124(1): 106-10, 2014 Jul 03.
Article
em En
| MEDLINE
| ID: mdl-24787007
ABSTRACT
Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor α (IL7R) or cytokine receptor-like factor 2 (CRLF2) have been described in acute lymphoblastic leukemias. Here we report noncysteine in-frame mutations in IL7R and CRLF2 located in a region of the TMD closer to the cytosolic domain. Biochemical and functional assays showed that these are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells in vitro and are transforming in vivo. Protein fragment complementation assays suggest that despite the absence of cysteines, the mechanism of activation is through ligand-independent dimerization. Mutagenesis experiments and ConSurf calculations suggest that the mutations stabilize the homodimeric conformation, positioning the cytosolic kinases in predefined orientation to each other, thereby inducing spontaneous receptor activation independently of external signals. Hence, type I cytokine receptors may be activated in leukemia through 2 types of transmembrane somatic dimerizing mutations.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores de Citocinas
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Receptores de Interleucina-7
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Mutação
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article