Science and Research

IRF4 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, 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.

  • Das Gupta, D.
  • Paul, C.
  • Samel, N.
  • Bieringer, M.
  • Staudenraus, D.
  • Marini, F.
  • Raifer, H.
  • Menke, L.
  • Hansal, L.
  • Camara, B.
  • Roth, E.
  • Daum, P.
  • Wanzel, M.
  • Mernberger, M.
  • Nist, A.
  • Bauer, U. M.
  • Helmprobst, F.
  • Buchholz, M.
  • Roth, K.
  • Bastian, L.
  • Hartmann, A. M.
  • Baldus, C.
  • Ikuta, K.
  • Neubauer, A.
  • Burchert, A.
  • Jäck, H. M.
  • Klein, M.
  • Bopp, T.
  • Stiewe, T.
  • Pagenstecher, A.
  • Lohoff, M.
Publication details
DOI: 10.1038/s41418-022-01005-z
Journal: Cell Death Differ
Work Type: Original
Location: UGMLC
Disease Area: LC
Partner / Member: UMR
Access-Number: 35459909

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