Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor a (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

Shochat, C., Tal, N., Gryshkova, V., Birger, Y., Bandapalli, O., Cazzaniga, G., et al. (2014). Novel activating mutations lacking cysteine in type i cytokine receptors in acute lymphoblastic leukemia. BLOOD, 124(1), 106-110 [10.1182/blood-2013-10-529685].

Novel activating mutations lacking cysteine in type i cytokine receptors in acute lymphoblastic leukemia

Cazzaniga, G;Biondi, A;
2014

Abstract

Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor a (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
Articolo in rivista - Articolo scientifico
Amino Acid Sequence; Animals; Base Sequence; Blotting, Western; Cells, Cultured; Cysteine; DNA Mutational Analysis; Female; Flow Cytometry; Heterografts; Humans; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Mutagenesis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Cytokine; Receptors, Interleukin-7; Signal Transduction; Transduction, Genetic; Mutation; Hematology; Biochemistry; Cell Biology; Immunology; Medicine (all)
English
2014
124
1
106
110
none
Shochat, C., Tal, N., Gryshkova, V., Birger, Y., Bandapalli, O., Cazzaniga, G., et al. (2014). Novel activating mutations lacking cysteine in type i cytokine receptors in acute lymphoblastic leukemia. BLOOD, 124(1), 106-110 [10.1182/blood-2013-10-529685].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/74904
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