LncRNA-NA2332/CUEDC2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）是白血病患者缓解后复发的根源，有效清除LSC是白血病治疗的难点。大部分研究支持LSC起源于造血干/祖细胞关键通路失调。JAK1-STAT3通路过激活是干/祖细胞向LSC转化的关键因素之一。我们前期研究提示CUEDC2下调介导的JAK1-STAT3通路过激活在LSC的干性维持和AML的发生发展中起重要作用，但是其下调机制尚未见报道。通过基因芯片，我们发现长链非编码RNA-NA2332参与JAK1-STAT3通路调控并且是CUEDC2潜在的负调控子。进一步研究显示NA2332在AML细胞中高表达，竞争抑制其表达则CUEDC2表达上调，抑制白血病细胞的增殖。本课题拟采用离体和在体模型，从表观遗传学、转录和转录后水平探索NA2332调控CUEDC2以及JAK1-STAT3通路的机制，明确其在LSC干性维持和AML发生发展中的作用。如期完成，有望加深对白血病发病和LSC的认识。

Leukemia stem cells (LSC) are the origins of relapse occuring in leukemia patients after remission, and effective removal of LSC is difficult in leukemia therapy. Most studies supported that the LSC might be orginated from the dysregulation of the key signaling pathway in the differentiation of hemopoietic stem cell/hemopoietic progenitor cell. The hyperactivation of JAK1-STAT3 signaling pathway is the key factor responsible for the transformation of hemopoietic stem cell/hemopoietic progenitor cell to LSC. Our previous studies suggested that the hyperactivation of JAK1-STAT3 mediated by the downregulation of CUEDC2 played critical roles in the maintenance of stem cell self-renewal and the pathogenesis of acute myeloid leukemia (AML). However, the exact mechanism of CUEDC2 downregulation in AML has not been reported previously. Through gene chip analysis, we found the long noncoding RNA-NA2332 was closely related to the regulation of JAK1-STAT3 signaling pathway. Moreover, the Lnc-RNA NA2332 was a potential negative regulator of CUEDC2. Further studies indicated that the higher expression of NA2332 was observed in AML cells and competitive inhibition of its’ expression enhanced the expression of CUEDC2 and affected the proliferation of AML cell lines. In the project, we propose to elucidate the regulation mechanism of NA2332 on the expression of CUEDC2 and the activation of JAK1-STAT3 signaling pathway in the epigenetic, transcription and post-transcription level using in vivo and in vitro model, and then explicit the role of NA2332 in the maintenance of stem cell self-renewal and the pathogenesis of AML. If finished on schedule, this study may enhance our understanding on the pathogenesis of leukemia and characteristics of LSC.