Oncogenic basic amino acid insertions at the extracellular juxtamembrane region of IL7RA cause receptor hypersensitivity

The receptor for interleukin-7 (IL-7) is formed by the IL7RA and the IL2RG (γc) chains. IL-7 leads to the reciprocal phosphorylation of IL7RA-associated JAK1 and γc-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 γc. 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 γc but with greatly increased sensitivity to IL-7.