Hematopoietic stem cells (HSCs) are susceptible to replication stress, which is a major contributor to HSC defects in Fanconi anemia (FA). Here, we report that HSCs relax the global chromatin by downregulating the expression of a chromatin architectural protein, DEK, in response to replication stress. DEK is abnormally accumulated in bone marrow (BM) CD34+ cells from patients with FA and in Fancd2-deficient HSCs. DEK haploinsufficiency promotes chromatin relaxation, replication stress relief, and function recovery of Fancd2-deficient HSCs. Furthermore, inhibition of DEK restores the proliferation of FA CD34+ cells in vitro and enhances their engraftment in vivo. Mechanistically, the activating transcription factor 2 (ATF2), specifically phosphorylated ATF2 at Thr69/71, was identified as a promoter of DEK transcription. Fancd2 deficiency results in p38 hyperphosphorylation, which in turn phosphorylates ATF2 at Thr69/71, leading to DEK accumulation in HSCs. In conclusion, our findings establish a functional link between chromatin relaxation and replication stress tolerance in HSCs and highlight DEK as a target for FA.
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January 21 2025
Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia
Zhe Chen
,
Zhe Chen
*
(Investigation, Writing - original draft, Writing - review & editing)
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
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Feng Wu
,
Feng Wu
*
(Investigation)
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
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Yan Li
,
Yan Li
*
(Investigation)
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
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Lei Li
,
Lei Li
*
(Investigation)
2
School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
3
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University
, Chongqing, China
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Yufei Lei
,
Yufei Lei
(Investigation)
2
School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
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Siwei Gao
,
Siwei Gao
(Investigation)
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
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Tao Chen
,
Tao Chen
(Investigation)
4
School of Medicine, Guizhou University
, Guiyang, China
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Yuxin Xie
,
Yuxin Xie
(Investigation)
2
School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
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Jianwen Xiao
,
Jianwen Xiao
(Investigation)
5Department of Hematology and Oncology,
Children’s Hospital, Chongqing Medical University
, Chongqing, China
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Hanqing Zeng
,
Hanqing Zeng
(Investigation)
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
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Jianchuan Deng
,
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
Jianchuan Deng: [email protected]
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Xueya Zhao
,
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
Xueya Zhao: [email protected]
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Yu Hou
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
6
Chongqing Key Laboratory of Hematology and Microenvironment
, Chongqing, China
Correspondence to Yu Hou: [email protected]
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Zhe Chen
Investigation, Writing - original draft, Writing - review & editing
*
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
2
School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
3
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University
, Chongqing, China
Yufei Lei
Investigation
2
School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
Siwei Gao
Investigation
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
Tao Chen
Investigation
4
School of Medicine, Guizhou University
, Guiyang, China
Yuxin Xie
Investigation
2
School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
Jianwen Xiao
Investigation
5Department of Hematology and Oncology,
Children’s Hospital, Chongqing Medical University
, Chongqing, China
Hanqing Zeng
Investigation
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
1Department of Hematology,
The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University
, Chongqing, China
6
Chongqing Key Laboratory of Hematology and Microenvironment
, Chongqing, China
Correspondence to Yu Hou: [email protected]
Xueya Zhao: [email protected]
Jianchuan Deng: [email protected]
*
Z. Chen, F. Wu, Y. Li, and L. Li contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
July 22 2024
Revision Received:
November 11 2024
Accepted:
December 19 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
Chongqing Science Fund
- Award Id(s): CSTB2022NSCQ-JQX0032,CSTB2023NSCQ-LZX0052
Funder(s):
Doctor Research Project of Chongqing
- Award Id(s): CSTB2022BSXM-JCX0005
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 82170115
Funder(s):
Chongqing Medical University
- Award Id(s): W0156
Funder(s):
Chongqing Municipal Education Commission
- Award Id(s): KJQN202400465
© 2025 Chen et al.
2025
Chen et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (3): e20241248.
Article history
Received:
July 22 2024
Revision Received:
November 11 2024
Accepted:
December 19 2024
Citation
Zhe Chen, Feng Wu, Yan Li, Lei Li, Yufei Lei, Siwei Gao, Tao Chen, Yuxin Xie, Jianwen Xiao, Hanqing Zeng, Jianchuan Deng, Xueya Zhao, Yu Hou; Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia. J Exp Med 3 March 2025; 222 (3): e20241248. doi: https://doi.org/10.1084/jem.20241248
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