Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche
Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche
复制标题
DOI：
10.1038/ncb3625
复制
发表时间：
2017-11-01
影响因子：
21.3
通讯作者：
Bhatia, Mickie
中科院分区：
文献类型：
--
作者：
Boyd, Allison L.;Reid, Jennifer C.;Bhatia, Mickie
急性髓性白血病（AML）的特征在于产生功能障碍的白血病原始细胞，并且患者特征性地患有由于正常骨髓-红细胞生成不足而导致的致命性感染和贫血。通过积累白血病细胞直接物理性地拥挤骨髓（BM）并不能完全解释这种造血功能衰竭。在这里，来自AML患者的分析应用于体外共培养平台和体内异种移植物建模，揭示了人类AML疾病特异性地破坏BM中的脂肪细胞生态位。骨髓脂肪细胞的白血病抑制导致内源性造血干细胞和祖细胞的调节失衡，导致骨髓-红细胞成熟受损。体内给予PPAR γ激动剂诱导BM脂肪生成，这在抑制白血病生长的同时拯救了健康的造血成熟。我们的研究确定了BM脂肪生成和正常骨髓-红细胞成熟之间以前未被认识的轴，其在治疗上可通过非细胞自主靶向小生境来改善AML中BM衰竭的症状。
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 PPAR gamma 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.