Critical roles of the miR-17∼92 family in thymocyte development, leukemogenesis, and autoimmunity
Kunyu Liao, Pengda Chen, Mengdi Zhang, Jia‐Zhen Wang, Teri Hatzihristidis, Xiaoxi Lin, Yang Liang, Nan Yao, Chenfeng Liu, Yazhen Hong, Xia Li, Hong Liu, Juan Carlos Zúñiga‐Pflücker, Paul E. Love, Xiang Chen, Wen‐Hsien Liu, Bin Zhao, Changchun Xiao
Abstract
Thymocyte development requires precise control of PI3K-Akt signaling to promote proliferation and prevent leukemia and autoimmune disorders. Here, we show that ablating individual clusters of the miR-17∼92 family has a negligible effect on thymocyte development, while deleting the entire family severely impairs thymocyte proliferation and reduces thymic cellularity, phenocopying genetic deletion of Dicer. Mechanistically, miR-17∼92 expression is induced by Myc-mediated pre-T cell receptor (TCR) signaling, and miR-17∼92 promotes thymocyte proliferation by suppressing the translation of Pten. Retroviral expression of miR-17∼92 restores the proliferation and differentiation of Myc-deficient thymocytes. Conversely, partial deletion of the miR-17∼92 family significantly delays Myc-driven leukemogenesis. Intriguingly, thymocyte-specific transgenic miR-17∼92 expression does not cause leukemia or lymphoma but instead aggravates skin inflammation, while ablation of the miR-17∼92 family ameliorates skin inflammation. This study reveals intricate roles of the miR-17∼92 family in balancing thymocyte development, leukemogenesis, and autoimmunity and identifies those microRNAs (miRNAs) as potential therapeutic targets for leukemia and autoimmune diseases.