Mechanisms of regulation by RNA in acute myeloid leukemia

 描述(由申请人提供)：这项名为“急性髓系白血病的RNA调控机制”的提案是为了响应美国国家癌症研究所颁发的PAR-14-267“杰出研究者奖(R35)”而提交的。这样做的目的是让有经验的调查人员能够进行特殊的研究，并更具冒险精神。近年来，研究人员发现，复杂生物体的很大一部分基因组是转录的，但不是翻译的。这些非编码RNA(NcRNAs)为许多生物过程提供了一个额外的、相对未被探索的控制层。虽然许多研究人员现在正转向对ncRNAs，特别是microRNAs的分类和研究，但有几个领域还没有得到广泛的研究。(1)第一类是反义RNA在限制肿瘤抑制基因，特别是主转录因子的表达中的作用。(2)在这个为总DNA基因组测序以寻找突变存在的时代，尤其是在癌症中，大多数研究人员不认为基因组还有另一层修饰，即RNA编辑，这已被证明在癌症中发挥了作用。(3)最重要的是，许多研究人员正在研究基因组的表观遗传修饰，特别是DNA甲基化，认为这些修饰控制着基因组的活动。对RNA(即转录)在控制表观遗传标记中的潜在作用的关注相对较少。这项提案的总体目标是调查这3部小说和 对癌症中RNA控制方面的探索不足，重点放在急性髓系白血病(AML)作为其他肿瘤类型的模型。因此，本建议将研究RNA生物学在癌症中的作用，重点放在三个新的领域：(1)限制肿瘤抑制基因PU1表达的非编码RNA的研究，特别是探讨其在核心结合因子白血病中的作用。随着时间的允许，其他反义RNA将被识别出来。(2)将研究RNA编辑失调在AML中的作用，特别是在核心结合因子白血病中RNA编辑酶ADAR2的抑制，以及ADAR3的错误表达。(3)将更详细地研究ncRNA对DNA甲基化等表观遗传变化的调控能力，目标是开发基因选择性去甲基化工具，以及识别受ncRNA调控的其他表观遗传标记。除了探索RNA生物学的新领域外，这些研究将在任何情况下都寻求调查它们在癌症中的作用，以及使用AML作为模型疾病，开发更具体的治疗方式的可能性。

 DESCRIPTION (provided by applicant): This proposal, "Mechanisms of regulation by RNA in acute myeloid leukemia", is being submitted in response to PAR-14-267, "Outstanding Investigator Award (R35)", from the National Cancer Institute. The objective is to allow experienced investigators to conduct exceptional research and be more adventurous. In recent years researchers have revealed that a large portion of the genome of complex organisms are transcribed but not translated. These noncoding RNAs (ncRNAs) provide an additional and relatively unexplored layer of control to many biological processes. While many investigators are now turning to categorizing and studying ncRNAs, especially microRNAs, there are several areas which have not been extensively studied. (1) The first is the role of antisense RNAs in limiting the expression of tumor suppressor genes, especially those of master transcription factors. (2) In this era of sequencing total DNA genomes for the presence of mutations, especially in cancer, most investigators do not consider that there is another layer of modification of the genome, that of RNA editing, and that this has been shown to play a role in cancer. (3) Most importantly, many investigators are studying epigenetic modifications of the genome, especially DNA methylation, with the view that these control genome activity. Relatively little attention has been given to the potential role of RNA (i.e., transcription) in controlling epigenetic marks. The overall goal of this proposal is to investigate these 3 novel and underexplored aspects of RNA control in cancer, focusing on acute myeloid leukemia (AML) as a model for other tumor types. Therefore, this proposal will study the role of RNA biology in cancer, focusing in three novel areas: (1) the study of a noncoding RNA which limits expression of the tumor suppressor PU.1, and in particular investigate its role in the core binding factor leukemias. As time permits, other antisense RNAs will be identified. (2) The role of dysregulation of RNA editing in AML will be investigated, and in particular the suppression of the RNA editing enzyme ADAR2 in core binding factor leukemias, and the misexpression of ADAR3. (3) The ability of ncRNA to regulate epigenetic changes such as DNA methylation will be studied in more detail, with the goals of developing gene-selective demethylating tools as well as identification of other epigenetic marks regulated by ncRNAs. In addition to exploring novel areas of RNA biology, these studies will in every instance seek to investigate their role in cancer, as well as potential development of more specific therapeutic modalities, using AML as a model disease.