LncRNA-RF6572/RFWD2在急性髓系白血病发生发展中的作用机制研究

白血病干细胞(LSC)是白血病患者复发的根源，有效清除LSC是其治疗的难点。多数研究支持LSC起源于造血干/祖细胞关键调控基因的失调，STAT3过激活是干/祖细胞向LSC转化的关键因素，虽然其过激活机制研究已较多，但STAT3因泛素化降解失调而过激活的机制鲜有报道。我们发现RFWD2低表达是STAT3泛素化降解失调的主要原因，但是其下调机制尚不清楚。结合长链非编码RNA研究的新进展，通过基因芯片，我们发现长链非编码RNA-RF6572在AML细胞中高表达且负调控RFWD2的表达；若下调其表达，RFWD2表达上调，促进STAT3泛素化降解，抑制AML细胞增殖，促进凋亡。为此，本课题拟采用离体和在体模型，从表观遗传、转录和转录后水平探索RF6572调控RFWD2表达调节STAT3泛素化和活性的机制，明确其在LSC干性维持和AML发生发展中的作用。如期完成，有望加深对LSC和AML发病的认识。

Leukemia stem cells (LSC) are the origins of relapse occurring in leukemia patients after remission, and effective removal of LSC is a big challenge in leukemia therapy. Most studies supported that LSC might be originated from dysregulation of the key regulation genes during the differentiation of hemopoietic stem/progenitor cells and STAT3 hyperactivation is the key factor involving in the transition of stem/progenitor cells to LSC. Although the role of STAT3 hyperactivation in the pathogenesis of acute myeloid leukemia (AML) has been widely studied, the exact mechanism by how STAT3 hyperactivation caused by the deregulation of ubiquitin mediated degradation remains unclear. Our study.indicated that the downregulation of RFWD2 in AML was the main reason for the deregulation of ubiquitin mediated degradation of STAT3 in AML. However, the mechanism of RFWD2 downregulation was still unclear. Considering the novel research progression of long chain non-coding RNA, through gene chip analysis, we found that the long noncoding RNA-RF6572 directly and positively regulated the expression of RFWD2 in the AML primary cell and cell line. Meanwhile, higher expression of RF6572 was observed in AML cells. Moreover, overexpression of RF6572 decreased the expression of RFWD2, inhibited the ubiquitin mediated degradation of STAT3, and thus promoted the proliferation of AML cell lines and inhibited cell apoptosis. In this project, we propose to elucidate the multi-interface regulation mechanism of RF6572 on the expression of RFWD2 thus regulated the ubiquitin mediated degradation and activity of STAT3 from epigenetic, transcriptional and post-transcriptional level using in vitro and in vivo model, aiming to explicit the role of RF6572 in the maintenance of LSC self-renewal as well as in the pathogenesis of AML. If finished on schedule, this study may enhance our understanding on the pathogenesis of AML and characteristics of LSC.