دورية أكاديمية
أعرض في EDS

RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition.

التفاصيل البيبلوغرافية
العنوان: RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition.
المؤلفون: Fan AC; Immunology Graduate Program.; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA., Nakauchi Y; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA., Bai L; Immunology Graduate Program., Azizi A; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; University of California Irvine School of Medicine, Irvine, California, USA., Nuno KA; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; Cancer Biology Graduate Program, Stanford University School of Medicine, Stanford, California, USA., Zhao F; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA., Köhnke T; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA., Karigane D; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA., Cruz-Hernandez D; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; Medical Research Council (MRC) Molecular Haematology Unit and Oxford Centre for Haematology, University of Oxford, Oxford, United Kingdom., Reinisch A; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; Division of Hematology, Medical University of Graz, Graz, Austria., Khatri P; Institute for Immunity, Transplantation and Infection, School of Medicine, and.; Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California, USA., Majeti R; Institute for Stem Cell Biology and Regenerative Medicine.; Cancer Institute.; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.
المصدر: The Journal of clinical investigation [J Clin Invest] 2023 Oct 02; Vol. 133 (19). Date of Electronic Publication: 2023 Oct 02.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Core Binding Factor Alpha 2 Subunit*/genetics , Interleukin-3*/genetics , Interleukin-3*/pharmacology , Leukemia*/drug therapy , Leukemia*/genetics, Humans ; Gene Expression Regulation ; Signal Transduction
مستخلص: Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood, and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we used primary patient samples and a RUNX1-KO model in primary human hematopoietic cells to investigate how RUNX1 loss contributes to leukemic progression and to identify targetable vulnerabilities. Surprisingly, we found that RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the IL-3 receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1-KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable targeting of these aggressive blood cancers with existing agents.
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فهرسة مساهمة: Keywords: Hematology; Hematopoietic stem cells; Human stem cells; Inflammation; Leukemias
المشرفين على المادة: 0 (Core Binding Factor Alpha 2 Subunit)
0 (Interleukin-3)
0 (RUNX1 protein, human)
تواريخ الأحداث: Date Created: 20230815 Date Completed: 20231011 Latest Revision: 20231016
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10541186
DOI: 10.1172/JCI167053
PMID: 37581927
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI167053