Abstract
Iron metabolism plays a crucial role in cell viability, but its relationship with adult stem cells and cancer stem cells is not fully understood. The ferritin complex, responsible for intracellular iron storage, is important in this process. We report that conditional deletion of ferritin heavy chain 1 (Fth1) in the hematopoietic system reduced the number and repopulation capacity of hematopoietic stem cells (HSCs). These effects were associated with a decrease in cellular iron level, leading to impaired mitochondrial function and the initiation of apoptosis. Iron supplementation, antioxidant, and apoptosis inhibitors reversed the reduced cell viability of Fth1-deleted hematopoietic stem and progenitor cells (HSPCs). Importantly, leukemic stem cells (LSCs) derived from MLL-AF9-induced acute myeloid leukemia (AML) mice exhibited reduced Fth1 expression, rendering them more susceptible to apoptosis induced by the iron chelation compared to normal HSPCs. Modulating FTH1 expression using mono-methyl fumarate increased LSCs resistance to iron chelator-induced apoptosis. Additionally, iron supplementation, antioxidant, and apoptosis inhibitors protected LSCs from iron chelator-induced cell death. Fth1 deletion also extended the survival of AML mice. These findings unveil a novel mechanism by which ferritin-mediated iron homeostasis regulates the survival of both HSCs and LSCs, suggesting potential therapeutic strategies for blood cancer with iron dysregulation.
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Data availability
The RNA-seq data generated in this study have been deposited in the GEO database under accession code GSE240742. Source data are provided with this paper.
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Acknowledgements
The animal facilities of Jinan university are appreciative acknowledged. The skillful assistance in flow cytometry of Xianda Chen and Wanling You are gratefully acknowledged. We would like to thank the members of the Zhenyu Ju’s laboratory for useful suggestions and excellent technical support. We would like to thank Xingguo Liu, Feixiang Bao and Xudong Zhu for their great assistance in mitochondria-related experiments. This work was supported by the grants 92049112, 81901403, 32300663, 82230047 from the National Natural Science Foundation of China, grant 2021YFA1100103 from the National Basic Research Program of China, grant 2023KCXTD004 from Innovation Team Project of Universities in Guangdong Province, and grant 20204BCJ22027 supported by Jiangxi Provincial Natural Science Foundation.
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W Yi, Y Huang and J Zhang performed the majority of experiments and analyzed the data. Q Zhan analyzed the RNA-Seq data and performed WB assay. M Zou participated in samples collection and preparation. H Cheng, S Tao and X Cheng supervised the leukemic stem cell-related experiments. Z Yin, F Wang, X Zhang and J Guo revised the manuscript. Z Ju and Z Chen designed and supervised the study. Z Chen wrote the manuscript.
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Yi, W., Zhang, J., Huang, Y. et al. Ferritin-mediated mitochondrial iron homeostasis is essential for the survival of hematopoietic stem cells and leukemic stem cells. Leukemia 38, 1003–1018 (2024). https://doi.org/10.1038/s41375-024-02169-y
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DOI: https://doi.org/10.1038/s41375-024-02169-y