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

Chen Shochat, Vitalina Gryshkova, Yehudit Birger, Obul R. Bandapalli, Giovanni Cazzaniga, Nava Gershman, Andreas E. Kulozik, Andrea Biondi, Marc R. Mansour, Jean Claude Twizere, Martina U. Muckenthaler, Nir Ben-Tal, Stefan N. Constantinescu, Dani Bercovich, Shai Izraeli*, Noa Tal

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)106-110
Number of pages5
JournalBlood
Volume124
Issue number1
DOIs
StatePublished - 3 Jul 2014

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