Gong Yuemin, Zhao Mei, Yang Wanzhu, Gao Ai, Yin Xiuxiu, Hu Linping, Wang Xiaofang, Xu Jing, Hao Sha, Cheng Tao, Cheng Hui
State Key Laboratory of Experimental Hematology, Tianjin, China.
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China; Collaborative Innovation Center for Cancer Medicine, Tianjin, China.
Exp Hematol. 2018 Apr;60:40-46.e2. doi: 10.1016/j.exphem.2017.12.010. Epub 2018 Jan 4.
Impaired production of healthy hematopoietic cells from residual hematopoietic stem cells (HSCs) leads to high mortality in acute myeloid leukemia (AML). Previous studies have identified p21 and Egr3 as intrinsic factors responsible for the growth arrest and differentiation blockade of normal HSCs in leukemia; however, the related extrinsic factors remain unknown. In this study, we found that transforming growth factor β (TGFβ) signaling was upregulated in HSCs from bone marrow of mice with MLL-AF9-induced acute myeloid leukemia (AML) because of excessive production of TGFβ1, especially from megakaryocytes, and overactivation of latent TGFβ1 protein. We also found that SMAD3, a signal transducer of TGFβ1, directly bound to Egr3 and upregulated its expression to arrest proliferation of HSCs. Our study provides evidence for targeting TGFβ1 in AML to rectify normal hematopoiesis defects in clinical practice.
残留造血干细胞（HSCs）产生健康造血细胞的功能受损会导致急性髓系白血病（AML）的高死亡率。先前的研究已确定p21和Egr3是导致白血病中正常HSCs生长停滞和分化阻滞的内在因素；然而，相关的外在因素仍然未知。在本研究中，我们发现，由于TGFβ1过度产生，尤其是来自巨核细胞，以及潜伏性TGFβ1蛋白的过度激活，在MLL-AF9诱导的急性髓系白血病（AML）小鼠骨髓的HSCs中，转化生长因子β（TGFβ）信号上调。我们还发现，TGFβ1的信号转导子SMAD3直接与Egr3结合并上调其表达，从而使HSCs的增殖停滞。我们的研究为在AML中靶向TGFβ1以纠正临床实践中的正常造血缺陷提供了证据。
