IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.

Autor:	Landberg N; Department of Medicine, Division of Hematology, Stanford School of Medi-cine, Stanford, California.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California., Köhnke T; Department of Medicine, Division of Hematology, Stanford School of Medi-cine, Stanford, California.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California., Feng Y; Department of Medicine, Division of Hematology, Stanford School of Medi-cine, Stanford, California.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California., Nakauchi Y; Department of Medicine, Division of Hematology, Stanford School of Medi-cine, Stanford, California.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California., Fan AC; Department of Medicine, Division of Hematology, Stanford School of Medi-cine, Stanford, California.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.; Immunology Graduate Program, Stanford University, Stanford, California., Linde MH; Department of Medicine, Division of Hematology, Stanford School of Medi-cine, Stanford, California.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.; Immunology Graduate Program, Stanford University, Stanford, California., Karigane D; Department of Medicine, Division of Hematology, Stanford School of Medi-cine, Stanford, California.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California., Lim K; Adelaide Medical School, University of Adelaide, Adelaide, Australia.; Precision Medicine, South Australian Health and Medical Research Institute, The University of Adelaide, Adelaide, Australia., Sinha R; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California., Malcovati L; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Department of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Thomas D; Adelaide Medical School, University of Adelaide, Adelaide, Australia.; Precision Medicine, South Australian Health and Medical Research Institute, The University of Adelaide, Adelaide, Australia., Majeti R; Department of Medicine, Division of Hematology, Stanford School of Medi-cine, Stanford, California.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.
Jazyk:	angličtina
Zdroj:	Blood cancer discovery [Blood Cancer Discov] 2024 Jan 23, pp. OF1-OF18. Date of Electronic Publication: 2024 Jan 23.
DOI:	10.1158/2643-3230.BCD-23-0195
Abstrakt:	Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia. Significance: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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