虽然它是治疗急性髓系白血病（AML）的有效方法，但化疗会导致骨髓抑制和造血重建不良。造血功能由骨髓（BM）内皮细胞（EC）调节，异基因造血干细胞移植后造血重建不良的急性白血病患者BM ECs功能障碍。因此，探索EC损伤的潜在机制并制定靶向治疗策略至关重要。研究发现，完全缓解的 AML 患者 (CR EC) 的 EC 中 TGF-β 信号传导上调，并导致 CR EC 损伤。施用TGF-β抑制剂可挽救体外由TGF-β1表达引起的ECs功能障碍，特别是其造血支持能力。此外，抑制TGF-β表达可以修复体外AML患者和AML-CR小鼠模型中化疗引发的BM EC损伤，并恢复正常造血功能，而不会促进AML进展。从机制上讲，我们的数据揭示了受损的 BM EC 转录组模式的改变，伴随着下游分子 TGF-βR1、pSmad2/3 以及与粘附、血管生成抑制和促凋亡相关的功能基因的过度表达。总的来说，我们的研究结果首次揭示了 TGF-β 信号的激活会导致 BM EC 功能障碍和造血重建不良。靶向 TGF-β 代表了一种促进多系造血的潜在治疗策略，从而使更多化疗后遭受骨髓抑制的癌症患者受益。版权所有 © 2024。由 Elsevier B.V. 出版。

Although it is an effective treatment for acute myeloid leukemia (AML), chemotherapy leads to myelosuppression and poor hematopoietic reconstruction. Hematopoiesis is regulated by bone marrow (BM) endothelial cells (ECs), and BM ECs are dysfunctional in acute leukemia patients with poor hematopoietic reconstitution after allogenic hematopoietic stem cell transplantation. Thus, it is crucial to explore the underlying mechanism of EC impairment and establish strategies for targeted therapy. TGF-β signaling was found to be upregulated in ECs from AML patients in complete remission (CR ECs) and led to CR EC damage. Administration of a TGF-β inhibitor rescued the dysfunction of ECs caused by TGF-β1 expression in vitro, especially their hematopoiesis-supporting ability. Moreover, inhibition of TGF-β expression repaired the BM EC damage triggered by chemotherapy in both AML patients in vitro and in an AML-CR murine model, and restored normal hematopoiesis without promoting AML progression. Mechanistically, our data reveal alterations in the transcriptomic pattern of damaged BM ECs, accompanied by the overexpression of downstream molecules TGF-βR1, pSmad2/3, and functional genes related to adhesion, angiogenesis suppression and pro-apoptosis. Collectively, our findings reveal for the first time that the activation of TGF-β signaling leads to BM EC dysfunction and poor hematopoietic reconstitution. Targeting TGF-β represents a potential therapeutic strategy to promote multilineage hematopoiesis, thereby benefiting more cancer patients who suffer from myelosuppression after chemotherapy.Copyright © 2024. Published by Elsevier B.V.