IRAIN-DNMT3A正反馈回路影响急性髓细胞白血病发生发展的分子机制及临床意义

长链非编码RNA的发现为深入揭示肿瘤发生的分子机制提供了全新的维度，但其影响急性髓系白血病（AML）发生发展的效应仍有待深入。长链非编码RNA IRAIN在AML中表达明显下降，但其失活的原因及其效应仍不清楚。前期研究我们发现IRAIN抑制AML细胞生长，与其抑制IGF-1R有关；而且DNA甲基转移酶DNMT3A在AML中表达升高且与IRAIN甲基化明显正相关，这提示DNMT3A可能是IRAIN失活的重要因子之一；同样重要的是，IRAIN失活后又可能通过促进MDM2表达进而上调DNMT3A的表达。由此我们推测在IRAIN与DNMT3A之间存在一条正反馈回路，该回路对AML的发生发展发挥了重要调控作用。本课题将进一步应用DNA甲基化测序及RNA干扰等手段验证该假设，并应用动物模型和临床标本验证该回路在体内对AML发生的影响，最终有望丰富AML发生的机制，并为AML诊治提供潜在的分子新靶标。

The discovery of long non-coding RNAs sheds a new light on further exploration of molecular mechanism for carcinogenesis, however, their role in the leukemogenesis for acute myeloid leukemia (AML) remains nearly unknown. A significant decreased expression of long non-coding RNA IRAIN was found in AML, but its resultant pathophysiological effects and its underlying mechanism need to be further explored. Our previous findings showed that IRAIN inhibited the growth of AML cells, and its inhibitory effects were supposed to be triggered by inhibition of IGF-1R. And then, increased expression of DNA methyltransferase DNMT3A was positively correlated with IRAIN promoter hypermethylation, suggesting that DNMT3A may be the underlying basis for the inactivation of IRAIN in AML. Furthermore, the inactivation of IRAIN may promote a higher expression of DNMT3A by enhancement of MDM2 expression. Based on the above data, we propose that a positive feedback circuitry exists between IRAIN and DNMT3A, which plays an important role in the leukemogenesis of AML. In the present study, the above hypothesis will be further investigated through multiple analysis like bisulfite sequencing and RNA interference assay, and then animal models and patients’ samples will be utilized to testify the impact of the dysregulation of IRAIN-DNMT3A circuitry on AML development. In summary, the results of the research will provide potential molecular targets for the diagnosis and therapy of AML.