biostudies-literatureDas Gupta DDeutsche ForschungsgemeinschaftDeutsche Krebshilfe2163-2176https://www.ebi.ac.uk/biostudies/studies/S-EPMC9613660biostudies-literatureUnknown29(11)The processes leading from disturbed B-cell development to adult B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remain poorly understood. Here, we describe Irf4^-/- mice as prone to developing BCP-ALL with age. Irf4^-/- preB-I cells exhibited impaired differentiation but enhanced proliferation in response to IL-7, along with reduced retention in the IL-7 providing bone marrow niche due to decreased CXCL12 responsiveness. Thus selected, preB-I cells acquired Jak3 mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to Jak3 mutants, devise a model to explain it, and describe structural and functional similarities to Jak2 mutations often occurring in human Ph-like ALL. Finally,Cell death and differentiationIRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity.PMC9613660LO 396/8-170112922Bauer UMBuchholz MRoth KBurchert ABastian LHartmann AMRoth ENist ASamel NDas Gupta DBopp TCamara BWanzel MBaldus CRaifer HStiewe TPaul CStaudenraus DHelmprobst FMenke LLohoff MKlein MIkuta KBieringer MJack HMDaum PPagenstecher ANeubauer AMarini FMernberger MHansal LfalseIRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity.The processes leading from disturbed B-cell development to adult B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remain poorly understood. Here, we describe Irf4^-/- mice as prone to developing BCP-ALL with age. Irf4^-/- preB-I cells exhibited impaired differentiation but enhanced proliferation in response to IL-7, along with reduced retention in the IL-7 providing bone marrow niche due to decreased CXCL12 responsiveness. Thus selected, preB-I cells acquired Jak3 mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to Jak3 mutants, devise a model to explain it, and describe structural and functional similarities to Jak2 mutations often occurring in human Ph-like ALL. Finally,2022-01-01T00:00:00Z2022 Nov2025-04-19T06:18:26.501Z2025-04-19T06:18:26.501ZS-EPMC96136603545990910.1038/s41418-022-01005-z