miR-17～92 microRNA家族在胸腺T细胞发育和T淋巴细胞白血病中的作用及致病机理研究

T cell development in the thymus is controlled by a multistep differentiation program under stringent quality control at multiple checkpoints. Dysregulation of molecular pathways controlling thymocyte development can cause immunodeficiency, thymocyte malignant transformation, and development of T cell acute lymphoblastic leukemia (T-ALL). Our understanding of the molecular events controlling T cell development and leukemogenesis remains limited. MicroRNAs (miRNAs) have recently emerged as major trans-factors that regulate the expression of protein coding genes. They control many diverse biological processes including cell differentiation, proliferation, and apoptosis. Hundreds of miRNAs are expressed in thymocytes, but it is unclear which ones are important for T cell development and malignant transformation. The miR-17~92 family comprises three miRNA clusters that encode 13 distinct miRNAs. Our preliminary studies show that miR-17~92 family miRNAs are highly expressed in thymocytes and T-ALL leukemia cells, that their LckCre-mediated conditional co-deletion in thymocytes caused a severe block of β-selection with a 10-fold reduction in CD4+CD8+ double positive (DP) thymocyte numbers, and that transgenic expression of miR-17~92 in mature T cells led to spontaneous T cell activation, proliferation, and fatal immunopathology. In this proposal, we will further investigate how miR-17~92 family miRNAs control T cell development and leukemogenesis, and elucidate the underlying molecular mechanisms. Upon the completion of this project, we expect to identify key miR-17~92 miRNAs and their downstream targets as novel therapeutic modalities or targets for the development of therapeutic interventions for the purpose of treating immunodeficiency and T-ALLs.

胸腺T细胞发育受阻或失控能够诱发严重的免疫缺陷或T淋巴细胞白血病(T-ALL)等疾病。厘清胸腺T细胞发育的调控机制对于揭示上述疾病的致病机理至关重要。miRNA在外周T细胞的功能逐渐被揭示，但在胸腺T细胞发育中的作用机制仍不清楚。本课题前期研究发现miR-17～92家族在胸腺T细胞和T-ALL的T细胞中均高丰度表达；miR-17～92家族缺失在小鼠中导致胸腺T细胞发育严重受阻，外周T细胞数量锐减；而T细胞特异性过表达miR-17～92转基因小鼠中T细胞会过度增殖活化。提示miR-17～92家族在胸腺T细胞发育和T-ALL中发挥关键作用。本课题将进一步揭示miR-17～92家族与Notch1，c-Myc，Pten和新的分子在胸腺T细胞发育和T-ALL中的互作和上下游调控方式。上述研究有望厘清miR-17～92家族在胸腺T细胞发育和T-ALL中的作用机理，为临床治疗提供新型干预靶点。

胸腺T细胞发育受阻或失控能够诱发严重的免疫缺陷或T淋巴细胞白血病(T-ALL)等疾病。.厘清胸腺T细胞发育的调控机制对于揭示上述疾病的致病机理至关重要。在过去的研究中microRNA在外周T细胞的功能逐渐被揭示，但在胸腺T细胞早期发育中的作用机制仍不清楚。本课题研究发现miR-17～92家族在DN到DP过渡阶段发挥关键作用，在胸腺T细胞发育早期敲除miR-17～92家族在DP阶段严重阻断T细胞发育。我们的分子机理研究阐明了miR-17～92家族通过Pten-p21这一条分子通路调控T细胞早期发育。