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.
