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

Cell Death Differ. 2022 Nov;29(11):2163-2176. doi: 10.1038/s41418-022-01005-z. Epub 2022 Apr 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • B-Lymphocytes
  • Burkitt Lymphoma* / pathology
  • Humans
  • Interleukin-7 / genetics
  • Janus Kinase 3 / genetics
  • Mice
  • Mutation / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Signal Transduction


  • Interleukin-7
  • JAK3 protein, human
  • Janus Kinase 3
  • interferon regulatory factor-4