Effects of IL-7Rα gain-of-function mutation (INS) are context dependent. Ectopic expression of mutant IL-7Rα alone in HSPCs originates oligoclonal myeloproliferative diseases (MPDs); when combined with constitutively active ICN1, it accelerates T-ALL; when expressed in CLPs, it drives mature B-cell ALL/lymphoma. Surprisingly, expression of INS in T-cell progenitors did not induce T-cell leukemia or lymphoproliferation.