On February 2025, Professor DENG Jianchuan’s team from the Department of Hematology at the Second Affiliated Hospital of Chongqing Medical University in collaboration with Professor HOU Yu and Associate Professor ZHAO Xueya from the College of Basic Medical College, published a significant research paper titled "Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia" in the prestigious medical journal, Journal of Experimental Medicine. This study not only provides new insights into the defect mechanisms of hematopoietic stem cells (HSCs) in Fanconi anemia (FA) but also identifies new therapeutic targets for intervention.
The research utilized multi-omics technologies including RNA-seq, ATAC-seq, and CUT&Tag-seq to map the response profile of HSCs under replication stress. It was discovered that HSCs adapt to replication stress by increasing chromatin accessibility and H3K27ac modifications. Conversely, restricting chromatin relaxation hinders the relief of replication stress, directly causing damage to the maintenance and hematopoietic functions of HSCs.
It was found that bone marrow CD34+ cells from FA patients exhibit significantly lower chromatin accessibility compared to normal samples, revealing an epigenetic mechanism underlying the impaired relief of replication stress in hematopoietic stem and progenitor cells of FA patients. Further mechanistic studies identified DEK, a chromatin architectural protein, as a critical effector limiting H3K27ac modification and chromatin accessibility. Moreover, it was confirmed that DEK is abnormally overexpressed in bone marrow CD34+ cells of FA patients. Knocking down DEK or treating with DEK inhibitors (such as the aptamer DTA-64) effectively enhances the hematopoietic function of CD34+ cells derived from FA patients both in vitro and in vivo. Mechanistically, activating transcription factor 2 (ATF2), specifically phosphorylated ATF2 at Thr69/71, was identified as a promoter of DEK transcription. Fancd2 deficiency results in hyperphosphorylation of p38, which subsequently phosphorylates ATF2 at Thr69/71, leading to DEK accumulation in HSCs. This breakthrough suggests potential strategies for restoring HSC function in FA through targeting DEK, providing new avenues for the treatment of this disease.
(Translated by AI)
