IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity
Description
<jats:title>Abstract</jats:title><jats:p>The processes leading from disturbed B-cell development to adult B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remain poorly understood. Here, we describe<jats:italic>Irf4</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>mice as prone to developing BCP-ALL with age.<jats:italic>Irf4</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>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<jats:italic>Jak3</jats:italic>mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to<jats:italic>Jak3</jats:italic>mutants, devise a model to explain it, and describe structural and functional similarities to<jats:italic>Jak2</jats:italic>mutations often occurring in human Ph-like ALL. Finally, targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established<jats:italic>Irf4</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>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.</jats:p>
Journal
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- Cell Death & Differentiation
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Cell Death & Differentiation 29 (11), 2163-2176, 2022-04-22
Springer Science and Business Media LLC
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Details 詳細情報について
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- CRID
- 1360017280648779136
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- ISSN
- 14765403
- 13509047
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- Data Source
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- Crossref
- KAKEN