AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth
AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth
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DOI：
10.1172/jci.insight.90036
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发表时间：
2017-07-06
期刊：
影响因子：
8
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
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作者：
Battula, V. Lokesh;Le, Phuong M.;Andreeff, Michael
骨髓(BM)微环境中的基因和表型改变，特别是骨祖细胞，已被证明支持白血病的发生。然而，目前尚不清楚白血病细胞如何改变骨髓微环境以创造一个友好的利基环境。在这里，我们报道了急性髓系白血病(AML)细胞，而不是正常的CD34(+)或CD33(+)细胞，可以诱导间充质基质细胞(MSCs)向成骨细胞分化。此外，AML细胞还能抑制MSCs的成脂分化。机制研究证实，AML来源的BMPs激活Smad1/5信号通路诱导MSCs向成骨方向分化。基因表达谱分析显示，AML细胞诱导BM-MSCs表达结缔组织生长因子(CTGF)，与AML类型无关。CTGF在转基因小鼠模型中的过表达极大地促进了白血病在体内的植入。综上所述，我们的数据表明，AML细胞在骨髓中诱导了一个富含成骨前细胞的生态位，进而促进了AML的扩张。
Genotypic and phenotypic alterations in the bone marrow (BM) microenvironment, in particular in osteoprogenitor cells, have been shown to support leukemogenesis. However, it is unclear how leukemia cells alter the BM microenvironment to create a hospitable niche. Here, we report that acute myeloid leukemia (AML) cells, but not normal CD34(+) or CD33(+) cells, induce osteogenic differentiation in mesenchymal stromal cells (MSCs). In addition, AML cells inhibited adipogenic differentiation of MSCs. Mechanistic studies identified that AML-derived BMPs activate Smad1/5 signaling to induce osteogenic differentiation in MSCs. Gene expression array analysis revealed that AML cells induce connective tissue growth factor (CTGF) expression in BM-MSCs irrespective of AML type. Overexpression of CTGF in a transgenic mouse model greatly enhanced leukemia engraftment in vivo. Together, our data suggest that AML cells induce a preosteoblast-rich niche in the BM that in turn enhances AML expansion.