دورية أكاديمية
Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics.
| العنوان: | Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics. |
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| المؤلفون: | Carter BZ; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bicarter@mdanderson.org., Mak PY; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tao W; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ayoub E; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ostermann LB; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Huang X; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Loghavi S; Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Boettcher S; Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland., Nishida Y; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ruvolo V; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hughes PE; Oncology Research, Amgen Inc, Thousand Oaks, CA, USA., Morrow PK; Amgen Inc, Thousand Oaks, CA, USA., Haferlach T; MLL Munich Leukemia Laboratory, Munich, Germany., Kornblau S; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Muftuoglu M; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Andreeff M; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mandreef@mdanderson.org. |
| المصدر: | Blood cancer journal [Blood Cancer J] 2023 Apr 24; Vol. 13 (1), pp. 57. Date of Electronic Publication: 2023 Apr 24. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101568469 Publication Model: Electronic Cited Medium: Internet ISSN: 2044-5385 (Electronic) Linking ISSN: 20445385 NLM ISO Abbreviation: Blood Cancer J Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Group |
| مواضيع طبية MeSH: | Leukemia, Myeloid, Acute*/drug therapy , Leukemia, Myeloid, Acute*/genetics , Leukemia, Myeloid, Acute*/metabolism , Antineoplastic Agents*/therapeutic use, Animals ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein ; bcl-2-Associated X Protein/metabolism ; bcl-2-Associated X Protein/pharmacology ; bcl-2-Associated X Protein/therapeutic use ; Apoptosis ; Cell Line, Tumor ; Proto-Oncogene Proteins c-bcl-2 |
| مستخلص: | TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic-driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation. (© 2023. The Author(s).) |
| التعليقات: | Erratum in: Blood Cancer J. 2023 May 17;13(1):80. (PMID: 37193700) |
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| معلومات مُعتمدة: | F32 CA271697 United States CA NCI NIH HHS; P30 CA016672 United States CA NCI NIH HHS |
| المشرفين على المادة: | N54AIC43PW (venetoclax) 0 (Myeloid Cell Leukemia Sequence 1 Protein) 0 (bcl-2-Associated X Protein) 97W7N9T08G (tapotoclax) 0 (Proto-Oncogene Proteins c-bcl-2) 0 (Antineoplastic Agents) |
| تواريخ الأحداث: | Date Created: 20230423 Date Completed: 20230425 Latest Revision: 20240125 |
| رمز التحديث: | 20240125 |
| مُعرف محوري في PubMed: | PMC10123065 |
| DOI: | 10.1038/s41408-023-00830-w |
| PMID: | 37088806 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 2044-5385 |
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| DOI: | 10.1038/s41408-023-00830-w |