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

Landberg, Niklas LU orcid ; Köhnke, Thomas ; Feng, Yang ; Nakauchi, Yusuke ; Fan, Amy C ; Linde, Miles H ; Karigane, Daiki ; Lim, Kelly ; Sinha, Rahul and Malcovati, Luca , et al. (2024) In Blood Cancer Discovery p.114-131
Abstract
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... (More)
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. (Less)
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publishing date
type
Contribution to journal
publication status
published
in
Blood Cancer Discovery
pages
114 - 131
external identifiers
  • pmid:38091010
  • scopus:85187376423
ISSN
2643-3249
DOI
10.1158/2643-3230.BCD-23-0195
language
English
LU publication?
no
id
02b18514-aed9-428d-a83b-d97724524cea
date added to LUP
2025-10-28 08:54:21
date last changed
2025-11-11 10:14:32
@article{02b18514-aed9-428d-a83b-d97724524cea,
  abstract     = {{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.}},
  author       = {{Landberg, Niklas and Köhnke, Thomas and Feng, Yang and Nakauchi, Yusuke and Fan, Amy C and Linde, Miles H and Karigane, Daiki and Lim, Kelly and Sinha, Rahul and Malcovati, Luca and Thomas, Daniel and Majeti, Ravindra}},
  issn         = {{2643-3249}},
  language     = {{eng}},
  month        = {{03}},
  pages        = {{114--131}},
  series       = {{Blood Cancer Discovery}},
  title        = {{IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation}},
  url          = {{http://dx.doi.org/10.1158/2643-3230.BCD-23-0195}},
  doi          = {{10.1158/2643-3230.BCD-23-0195}},
  year         = {{2024}},
}