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.
摘要：
胸腺细胞发育需要精确控制PI3K-Akt信号传导以促进增殖并预防白血病和自身免疫性疾病。这里,我们表明，消除miR-17~92家族的个体簇对胸腺细胞发育的影响可以忽略不计，同时删除整个家族严重损害胸腺细胞增殖和减少胸腺细胞，Dicer的表型遗传缺失。机械上,miR-17~92表达由Myc介导的前T细胞受体(TCR)信号诱导，miR-17~92通过抑制Pten的翻译促进胸腺细胞增殖。miR-17~92的逆转录病毒表达可恢复Myc缺陷胸腺细胞的增殖和分化。相反，miR-17~92家族的部分缺失显著延缓了Myc驱动的白血病发生。有趣的是，胸腺细胞特异性转基因miR-17~92表达不引起白血病或淋巴瘤，反而加重皮肤炎症，而miR-17~92家族的消融可改善皮肤炎症。这项研究揭示了miR-17~92家族在平衡胸腺细胞发育中的复杂作用，白血病发生,和自身免疫，并将这些微小RNA（miRNA）鉴定为白血病和自身免疫性疾病的潜在治疗靶标。
