Autor: |
Dennis Das Gupta, Christoph Paul, Nadine Samel, Maria Bieringer, Daniel Staudenraus, Federico Marini, Hartmann Raifer, Lisa Menke, Lea Hansal, Bärbel Camara, Edith Roth, Patrick Daum, Michael Wanzel, Marco Mernberger, Andrea Nist, Uta-Maria Bauer, Frederik Helmprobst, Malte Buchholz, Katrin Roth, Lorenz Bastian, Alina M Hartmann, Claudia Baldus, Koichi Ikuta, Andreas Neubauer, Andreas Burchert, Hans-Martin Jäck, Matthias Klein, Tobias Bopp, Thorsten Stiewe, Axel Pagenstecher, Michael Lohoff |
Rok vydání: |
2022 |
Popis: |
The processes leading from disturbed B cell development to adult B cell progenitor acute lymphoblastic leukemia (BCP-ALL) are 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. |
Databáze: |
OpenAIRE |
Externí odkaz: |
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