Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM. Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. In vivo administration of PPARγ agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth. Our study identifies a previously unappreciated axis between BM adipogenesis and normal myelo-erythroid maturation that is therapeutically accessible to improve symptoms of BM failure in AML via non-cell autonomous targeting of the niche.

中文翻译：

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急性髓细胞性白血病通过损害脂肪细胞的骨髓生境来破坏内源性骨髓红细胞生成。

急性髓细胞性白血病（AML）以功能异常的白血病母细胞的生成为特征，并且患者因正常的骨髓红细胞生成不足而遭受致命的感染和贫血。通过积聚白血病细胞直接进行骨髓的直接物理拥挤并不能完全解释这种造血功能衰竭。在这里，来自AML患者的分析被应用于体外共培养平台和体内异种移植模型，揭示了人类AML疾病特异地破坏了BM中的脂肪小生境。白血病对BM脂肪细胞的抑制导致内源性造血干细胞和祖细胞的调节不平衡，从而导致骨髓红系成熟度受损。体内给予PPARγ激动剂可诱导BM脂肪形成，挽救了健康的造血成熟，同时抑制了白血病的生长。我们的研究确定了BM脂肪形成和正常的骨髓-红系成熟之间的先前未曾察觉的轴，该轴可通过非利基自主定位来改善AML中BM衰竭的症状。