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

Abstract Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in Interleukin-7 receptor (IL7R) or cytokine receptor-like factor 2 (CRLF2) have been described in acute lymphoblastic leukemias (ALL). Here we report non-cysteine in-frame mutations in IL7R and CRLF2 located in a region of the TMD closer to the cytosolic domain. Biochemical and functional assays revealed 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 homo-dimeric 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 two types of transmembrane somatic dimerizing mutations. From