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Whether acute lymphoblastic leukemia (ALL)-related <jats:italic>IL7R<\/jats:italic> gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant <jats:italic>IL7R<\/jats:italic>, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as <jats:italic>Myc<\/jats:italic> or <jats:italic>Bcl2<\/jats:italic>, downregulation of tumor suppressors such as <jats:italic>Ikzf1<\/jats:italic> or <jats:italic>Arid2<\/jats:italic>, and major IL-7R signaling upregulation (involving JAK\/STAT5 and PI3K\/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous <jats:italic>IL7R<\/jats:italic> mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that <jats:italic>IL7R<\/jats:italic> can initiate this malignancy.<\/jats:p>","DOI":"10.1038\/s41467-021-27197-5","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T11:03:55Z","timestamp":1639479835000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Interleukin-7 receptor \u03b1 mutational activation can initiate precursor B-cell acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"12","author":[{"given":"Afonso R. 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