H/ACA Box orphan snoRNA SNORA73 特异性调控髓性细胞分化 的分子机制

急性早幼粒细胞白血病是急性髓细胞性白血病染色体易位的一类，由PML body组分PML与RARA 蛋白形成易位，产生原癌融合蛋白PML-RARA，导致分化受阻，引起细胞恶性增殖。我们前期研究APL相关的非编码RNA,发现与PML-RARA结合的非编码RNA分子中，丰度较高的是一个含有box H/ACA的orphan snoRNA SNORA73；初步细胞功能研究发现，该 snoRNA与PML-RARA 融合蛋白表达及髓性细胞分化有关，提示该snoRNA很可能在髓细胞性白血病中扮演重要角色。本项目在此基础上开展以下研究：（1）SNORA73在髓细胞性白血病中的功能；(2）SNORA73结合的非经典核糖核蛋白鉴定与功能；（3）SNORA73结合的非经典互作核糖核蛋白调控髓系细胞分化的机制；本项目的完成，不仅揭示orphan snoRNA新的功能，还可为白血病治疗提供新治疗靶标。

Acute Promyelocytic Leukemia is characterized by a specific t (15;17) chromosomal translocation, resulting in the fusion of the promyelocytic gene (PML) and the retinoic acid receptor alpha gene (RARA) into the oncoprotein PML-RARA, which represses promyelocytic to granulocytic differentiation. We previously found a box H/ACA orphan snoRNA, named as SNORA73 that interacted with PML-RARA. Further studies found that the snoRNA regulated the expression of oncoprotein PML-RARA and myeloid cell differentiation, suggesting that the ophan snoRNA may play an important role in myeloid leukemia. Based on these previous findings, the project proposed following studies: (1) the function of orphan snoRNA SNORA73 in myeloid leukemia; (2) the identification and validation of SNORA73 binding nonclassical ribonucleoproteins ; (3) regulatory mechanisms of the binding nonclassical proteins of SNORA73 in regulating myeloid cell differentiation. By revealing the function of orphan snoRNA SNORA73, the project would propose a new idea that orphan snoRNAs may be potential as a therapeutic target for leukemia.