Article (Scientific journals)
Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia.
Shochat, Chen; Tal, Noa; Gryshkova, Vitalina et al.
2014In Blood, 124 (1), p. 106-10
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Keywords :
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/genetics; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics; Receptors, Cytokine/genetics; Receptors, Interleukin-7/genetics; Signal Transduction/genetics; Transduction, Genetic
Abstract :
[en] Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor alpha (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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Shochat, Chen
Tal, Noa
Gryshkova, Vitalina
Birger, Yehudit
Bandapalli, Obul R.
Cazzaniga, Giovanni
Gershman, Nava
Kulozik, Andreas E.
Biondi, Andrea
Mansour, Marc R.
Twizere, Jean-Claude  ;  Université de Liège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Biologie cell. et moléc.
Muckenthaler, Martina U.
Ben-Tal, Nir
Constantinescu, Stefan N.
Bercovich, Dani
Izraeli, Shai
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Title :
Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia.
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American Society of Hematology, Washington, United States - District of Columbia
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Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2014 by The American Society of Hematology.
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