长链非编码RNA ANRIL在急性髓系白血病靶向治疗中的作用及机制研究

Acute myeloid leukemia(AML) is a hematopoietic stem cell clonal malignant disease with ascending morbidity. Currently, long non-coding RNA (lncRNA) has been known to be associated with the development and progression of carcinomas, including AML. It is also regarded as a potential biomarker for targeted therapy and cancer prognosis. Our preliminary results showed that lncRNA ANRIL was markedly up-regulated in AML patients compared to normal donors. Knockdown of ANRIL expression decreased the proliferation and enhanced the apoptosis of Kasumi-1 cells. Bioinformatics analysis suggested that ANRIL may promote the progression of AML through epigenetically modulation. To verify our hypothesis, we utilize technologies including RNA interfering, lentivirus mediated knockdown/over-expression, RIP and RNA pull-down,RNA-seq，mass spectrometric analysis and nude mice tracing in vivo to explore the role and mechnisms of ANRIL in apoptosis and epigenetic regulation on the molecular, cellular and system levels. The expressions of ANRIL in non-APL AML patients of de nova, relapsed ,refractory and different risk stratification will be further compared with healthy donors. These studies will help establish the potential candidacy of ANRIL as a biomarker for progression and prognosis in AML, supporting theoretical and experimental basis for the potential clinical application of ANRIL in judging prognosis and targeted therapy in non-APL AML.

急性髓系白血病（AML）是造血干细胞恶性克隆性疾病，发病率逐年上升，探寻其治疗靶点和预后分子标志一直是AML治疗研究的热点。长链非编码RNA是近年研究倍受关注的一类与肿瘤发生、发展和预后密切相关的RNA分子。前期结果提示ANRIL在AML患者中呈高表达；下调其表达可抑制细胞增殖，促进凋亡；生物信息学分析提示其可能通过基因转录、表观遗传修饰等途径影响AML发生发展及预后。本项目采用慢病毒载体调控、RNA pull-down， RIP、RNA测序、质谱及活体示踪等技术，体内外(试)实验结合研究ANRIL在AML靶向治疗中的作用及可能机制；比较健康供者、初诊、复发、难治及不同危险分层非M3-AML患者的ANRIL表达水平，探讨作为AML疾病危险分层和疾病发生发展标志的可行性。研究将为ANRIL作为非M3-AML治疗靶点、预后标志等潜在的临床应用和丰富血液肿瘤的精准诊疗提供理论和实验依据。