| First Author | Das Gupta D | Year | 2022 |
| Journal | Cell Death Differ | Volume | 29 |
| Issue | 11 | Pages | 2163-2176 |
| PubMed ID | 35459909 | Mgi Jnum | J:330712 |
| Mgi Id | MGI:7384164 | Doi | 10.1038/s41418-022-01005-z |
| Citation | Das Gupta D, et al. (2022) IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity. Cell Death Differ 29(11):2163-2176 |
| abstractText | 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, targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4(-/-) leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. In this work, we present spontaneous leukemogenesis following IRF4 deficiency with potential implications for high-risk BCP-ALL in adult humans. |
