Agradecimentos: The authors thank Laurent Knoops (Université Catholique de Louvain, Louvain-la-Neuve, Belgium), Thierry Rose (Institut Pasteur, Paris, France), and Isabelle Lucet (Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia) for kindly providing the pLHRE-luc plasmid, human ?c clone, and the human JAK3 clone, respectively.This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (12/12802-1 and 14/20015-5) (J.A.Y.) and (10/16947-9 and 13/08293-7) (L.M.), and by a grant from the National Health and Medical Research Council of Australia (APP1084797) (A.J.B.). L.W.C., G.O.L.R., and L.L.A. received scholarships from Fundação de Amparo à Pesquisa do Estado de São Paulo. L.G.P. received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. J.A.Y. received a Productivity Fellowship from the Brazilian National Counsel of Technological and Scientific Development (CNPq 305896/2013-0 and 301596/2017-4) Ver menos

Abstract: The receptor for interleukin-7 (IL-7) is formed by the IL7RA and the IL2RG (?c) chains. IL-7 leads to the reciprocal phosphorylation of IL7RA-associated JAK1 and ?c-associated JAK3, followed by phosphorylation of IL7RA and then STAT5 anchoring and activation. Constitutive signaling mutants of IL7RA were described in acute lymphoblastic leukemia (ALL). So far, the mutations studied include extracellular juxtamembrane (EJM) cysteine insertions1-3 and transmembrane (TM) cysteine that lacks insertions,4 both of which enable homodimer formation and constitutive signaling independently of cytokine and ?c. In this study, we describe another class of IL7RA mutation characterized by the insertion of positively charged amino acids in the EJM region of the receptor. In contrast to the cysteine EJM and TM insertion mutations, the EJM charged residue mutations are able to activate signaling and confer proliferative advantage only in the presence of both IL-7 and ?c but with greatly increased sensitivity to IL-7 Ver menos