Megakaryocyte-derived excessive transforming growth factor β1 inhibits proliferation of normal hematopoietic stem cells in acute myeloid leukemia

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 beta (TGF beta) signaling was upregulated in HSCs from bone marrow of mice with MLL-AF9-induced acute myeloid leukemia (AML) because of excessive production of TGF beta 1, especially from megakaryocytes, and overactivation of latent TGF beta 1 protein. We also found that SMAD3, a signal transducer of TGF beta 1, directly bound to Egr3 and upregulated its expression to arrest proliferation of HSCs. Our study provides evidence for targeting TGF beta 1 in AML to rectify normal hematopoiesis defects in clinical practice. (C) 2018 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license