Battula V Lokesh, Le Phuong M, Sun Jeffrey C, Nguyen Khoa, Yuan Bin, Zhou Ximin, Sonnylal Sonali, McQueen Teresa, Ruvolo Vivian, Michel Keith A, Ling Xiaoyang, Jacamo Rodrigo, Shpall Elizabeth, Wang Zhiqiang, Rao Arvind, Al-Atrash Gheath, Konopleva Marina, Davis R Eric, Harrington Melvyn A, Cahill Catherine W, Bueso-Ramos Carlos, Andreeff Michael
Molecular Hematology and Therapy, Department of Leukemia.
Department of Breast Medical Oncology.
JCI Insight. 2017 Jul 6;2(13). doi: 10.1172/jci.insight.90036.
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.
骨髓（BM）微环境，尤其是骨祖细胞中的基因型和表型改变，已被证明可支持白血病的发生。然而，尚不清楚白血病细胞如何改变骨髓微环境以创造一个适宜的微环境。在这里，我们报告急性髓系白血病（AML）细胞，而非正常的CD34+或CD33+细胞，可诱导间充质基质细胞（MSC）发生成骨分化。此外，AML细胞抑制了MSC的脂肪生成分化。机制研究表明，AML来源的骨形态发生蛋白（BMP）激活Smad1/5信号通路，从而诱导MSC发生成骨分化。基因表达阵列分析显示，无论AML类型如何，AML细胞均可诱导BM-MSC中结缔组织生长因子（CTGF）的表达。在转基因小鼠模型中过表达CTGF可显著增强体内白血病细胞的植入。总之，我们的数据表明，AML细胞在骨髓中诱导形成富含前成骨细胞的微环境，进而促进AML的扩增。
