@article{Lyu_Tang_Xing_Zhou_Lv_Fu_Wang_Xu_Zhang_Lee_Kong_Huang_2022, place={Pavia, Italy}, title={The glycolytic enzyme PFKFB3 determines bone marrow endothelial progenitor cell damage after chemotherapy and irradiation}, volume={107}, url={https://haematologica.org/article/view/haematol.2021.279756}, DOI={10.3324/haematol.2021.279756}, abstractNote={<p>Bone marrow (BM) endothelial progenitor cell (EPC) damage of unknown mechanism delays the repair of endothelial cells (EC) and recovery of hematopoiesis after chemo-radiotherapy. We found increased levels of the glycolytic enzyme PFKFB3 in the damaged BM EPC of patients with poor graft function, a clinical model of EPC damage-associated poor hematopoiesis after allogeneic hematopoietic stem cell transplantation. Moreover, in vitro the glycolysis inhibitor 3-(3-pyridinyl)- 1-(4-pyridinyl)-2-propen-1-one (3PO) alleviated the damaged BM EPC from patients with poor graft function. Consistently, PFKFB3 overexpression triggered BM EPC damage after 5-fluorouracil treatment and impaired hematopoiesis-supporting ability in vitro. Mechanistically, PFKFB3 facilitated pro-apoptotic transcription factor FOXO3A and expression of its downstream genes, including p21, p27, and FAS, after 5-fluorouracil treatment in vitro. Moreover, PFKFB3 induced activation of NF-κB and expression of its downstream adhesion molecule E-selectin, while it reduced hematopoietic factor SDF-1 expression, which could be rescued by FOXO3A silencing. High expression of PFKFB3 was found in damaged BM EC of murine models of chemo-radiotherapy-induced myelosuppression. Furthermore, a murine model of BM EC-specific PFKFB3 overexpression demonstrated that PFKFB3 aggravated BM EC damage, and impaired the recovery of hematopoiesis after chemotherapy in vivo, effects which could be mitigated by 3PO, indicating a critical role of PFKFB3 in regulating BM EC damage. Clinically, PFKFB3-induced FOXO3A expression and NF-κB activation were confirmed to contribute to the damaged BM EPC of patients with acute leukemia after chemotherapy. 3PO repaired the damaged BM EPC by reducing FOXO3A expression and phospho-NF-κB p65 in patients after chemotherapy. In summary, our results reveal a critical role of PFKFB3 in triggering BM EPC damage and indicate that endothelial-PFKFB3 may be a potential therapeutic target for myelosuppressive injury.</p&gt;}, number={10}, journal={Haematologica}, author={Lyu, Zhong-Shi and Tang, Shu-Qian and Xing, Tong and Zhou, Yang and Lv, Meng and Fu, Hai-Xia and Wang, Yu and Xu, Lan-Ping and Zhang, Xiao-Hui and Lee, Hsiang-Ying and Kong, Yuan and Huang, Xiao-Jun}, year={2022}, month={Oct.}, pages={2365-2380} }