IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.

IF 11.5 Q1 HEMATOLOGY
Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti
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Abstract

Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of 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 (HSCs). 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 complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent development and relapse of leukemia.

抑制氧化磷酸化可消除 IDH1 突变的白血病前期造血干细胞。
罕见的白血病前造血干细胞(pHSCs)仅携带起始突变,可在诊断急性髓细胞性白血病时检测到。pHSCs是白血病的起源,也是潜在的复发库。我们利用原始人类样本和基因编辑技术建立了异柠檬酸脱氢酶1(IDH1)突变pHSCs模型,显示了pHSCs与健康造血干细胞(HSCs)在表观遗传、转录和代谢方面的差异。我们证实,IDH1驱动的克隆造血与全血细胞减少有关,这表明完全重建造血存在固有缺陷。尽管IDH1突变的pHSCs能进行多系移植,但它们的增殖能力减弱、分化受阻、MHC II类基因下调、氧化磷酸化代谢重编程。重要的是,抑制氧化磷酸化可完全清除IDH1突变的pHSCs,但不能清除IDH2突变的pHSCs或野生型造血干细胞。我们的研究结果表明,IDH1突变的白血病前期克隆可以用复合体I抑制剂作为靶点,为预防白血病的发展和复发提供了一种潜在的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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