Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML.

中文翻译：

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抑制骨内血管微环境重塑可挽救 AML 中的造血干细胞损失。

骨髓血管微环境维持造血干细胞（HSC）的生命，并在白血病中被彻底重塑以支持病理功能。急性髓性白血病 (AML) 细胞产生血管生成因子，这可能有助于这种重塑，但抗血管生成疗法并不能改善 AML 患者的预后。使用活体显微镜，我们发现 AML 进展导致中央和骨内骨髓区域脉管系统的差异重塑。骨内AML细胞产生促炎和抗血管生成细胞因子，并逐渐降解骨内内皮、基质细胞和成骨细胞，而中央骨髓保持血管化，脾血管微环境扩张。重塑的骨内膜区域支持非白血病 HSC 的能力降低，与正常造血功能的丧失相关。用小分子去铁胺或基因方法保护骨内皮内皮可以挽救 HSC 的损失，提高化疗效果并提高生存率。这些发现表明，防止骨内膜血管系统降解可能会改善当前治疗 AML 的范例。