4.7 Article

IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity

Journal

CELL DEATH AND DIFFERENTIATION
Volume 29, Issue 11, Pages 2163-2176

Publisher

SPRINGERNATURE
DOI: 10.1038/s41418-022-01005-z

Keywords

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Funding

  1. German Cancer Aid, Mildred-Scheel doctoral scholarship [70112922]
  2. Deutsche Forschungsgemeinschaft (DFG) [LO 396/8-1]
  3. Else Kroner-Fresenius-Stiftung
  4. Projekt DEAL

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This study finds that Irf4(-/-) mice are prone to developing BCP-ALL, and further investigates the impaired differentiation but enhanced proliferation of Irf4(-/-) preB-I cells, possibly due to Jak3 mutations.
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.

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