biostudies-literatureChen ZChongqing Science FundChongqing Medical UniversityDoctor Research Project of ChongqingNational Natural Science Foundation of ChinaChongqing Municipal Education Commissione20241248https://www.ebi.ac.uk/biostudies/studies/S-EPMC11748990biostudies-literatureUnknown222(3)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 The Journal of experimental medicineInhibition of DEK restores hematopoietic stem cell function in Fanconi anemia.PMC1174899082170115CSTB2022BSXM-JCX0005CSTB2022NSCQ-JQX0032KJQN202400465W0156CSTB2023NSCQ-LZX0052Xie YDeng JWu FLi LHou YZhao XLi YChen ZXiao JLei YZeng HGao SChen TfalseInhibition of DEK restores hematopoietic stem cell function in Fanconi anemia.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 2025-01-01T00:00:00Z2025 Mar2026-06-06T19:22:04.435Z2026-06-04T03:12:48.069ZS-EPMC117489903983608510.1084/jem.20241248