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STEM CELL BIOLOGY

HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses

Leukemia volume 36, pages 1123–1131 (2022)Cite this article

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Abstract

Hematopoietic stress drives quiescent hematopoietic stem cells (HSCs) to proliferate, generating reactive oxygen species (ROS) and oxidative DNA damage including abasic sites. Such a coupling between rapid DNA replication and a burst of abasic site formation during HSC stress responses, however, presents a challenge to accurately repair abasic sites located in replication-associated single-stranded DNA. Here we show that HMCES, a novel shield of abasic sites, plays pivotal roles in overcoming this challenge upon HSC activation. While HMCES was dispensable for steady-state hematopoiesis, Hmces-deficient HSCs exhibited compromised long-term self-renewal capacity in response to hematopoietic stress such as myeloablation and transplantation. Loss of HMCES resulted in accumulation of DNA lesions due to impaired resolution of abasic sites generated by activation-induced ROS in activated HSCs and broad downregulation of DNA damage response and repair pathways. Moreover, Hmces-deficient mice died from bone marrow failure after exposure to sublethal irradiation, which also produces ROS. Notably, dysregulation of HMCES occurs frequently in acute lymphocytic leukemia (ALL) and is associated with poor clinical outcomes. Together, our findings not only highlighted HMCES as a novel genome protector in activated HSCs, but also position it as a potential selective target against ALL while sparing normal hematopoiesis.

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Fig. 1: HMCES is dispensable for steady-state hematopoiesis.
Fig. 2: HMCES-deficient LT-HSCs exhibit compromised self-renewal capacity in stress hematopoiesis.
Fig. 3: HMCES depletion results in elevated DNA lesion upon LT-HSC activation.
Fig. 4: Loss of HMCES confers hypersensitivity to irradiation.
Fig. 5: HMCES deficiency leads to downregulation of DNA damage response (DDR) and repair genes in LT-HSCs.
Fig. 6: Elevated expression of HMCES occurs frequently in ALL and is associated with poor clinical outcome.

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Data availability

RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus database under accession number GSE150721.

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Acknowledgements

We thank Drs. Lei Li, Pinglong Xu, and Pengxu Qian for helpful comments and discussions. We are also grateful to Meilei Sheng, Shu Qiang and the core facility of Life Sciences Institute at Zhejiang University for technical assistance. This project was supported by National Natural Science Foundation of China (32022023, 31871478, 81770155, 82022026), National Key Research and Development Programs of China (2017YFC1001500, 2018YFA0109300, 2017YFA0103302), Zhejiang Provincial Natural Science Foundation of China (LR18C060001), Science Foundation for Distinguished Young Scholars of Guangdong Province (2019B151502008), and Fundamental Research Funds for the Central Universities.

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  1. These authors contributed equally: Yinghao Pan, Hongna Zuo.

Authors and Affiliations

  1. MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China

    Yinghao Pan, Fei Huang, Yezhang Zhu, Lanrui Cao, Qian-Qian Sha, Yang Li, Huiying Zhang, Miao Shi, Jun Huang, Heng-Yu Fan & Li Shen

  2. MOE Key Laboratory of Regenerative Medicine, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China

    Hongna Zuo, Fei Wen & Zhenyu Ju

  3. Department of Orthopedics Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Chengzhen Liang & Li Shen

  4. Clinical Research Unit, Children’s Hospital of Shanghai Jiaotong University, Shanghai, China

    Lin Zou

  5. Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Ageing Research, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China

    Hu Wang

  6. Hangzhou Innovation Center, Zhejiang University, Hangzhou, China

    Li Shen

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Contributions

LS, ZJ, and HW conceived and supervised the project; YP, HZ, FW, FH, YZ, LC, QS, YL, and MS performed the experiments and analyzed the data; LC, QS, and HF generated the Hmces−/− mice; LZ collected clinical samples; YP and LS wrote the manuscript with inputs from CL, JH, LZ, HF, ZJ, and HW, and all authors discussed the results and commented on the manuscript.

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Correspondence to Zhenyu Ju, Hu Wang or Li Shen.

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Pan, Y., Zuo, H., Wen, F. et al. HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses. Leukemia 36, 1123–1131 (2022). https://doi.org/10.1038/s41375-021-01499-5

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