The role of microRNAs in leukemic initiation and maintenance

描述（由申请人提供）：MicroRNAs是一种小的非编码rna，最近被认为是人类癌症中重要的分子调节因子。然而，尽管我们知道microRNA在急性髓性白血病（AML）中表达经常失调，但对microRNA在白血病起始和维持中的作用仍然知之甚少，这是我们的长期目标。根据我们之前的工作，我们试图了解microRNA在造血和人类癌症中的作用，在这里，我们的目标是了解一个特定的microRNA家族，miR-125 microRNA家族，在AML中的作用。我们发现miR-125家族microrna在造血细胞中显示出与转化相关的体外特性。此外，我们已经积累了进一步的证据表明这些microrna在AML白血病发生中的作用。通过在人类aml中广泛的microRNA表达谱分析，我们发现一个aml亚组的miR-125a或miR-125b水平显著升高。我们还发现，miR-125a在自我更新造血干细胞（hsc）中表达量很高。强迫表达miR-125a积极改变干细胞活性并拮抗凋亡通路。除了我们自己的工作外，也有报道称miR-125b-1在人类aml和骨髓增生异常综合征的一个亚群中易位。本提案的主要目标是通过开发和分析小鼠模型和人类细胞，确定miR-125家族microrna在白血病发生和维持中的作用。在Specific Aim 1中，我们将使用几种小鼠模型来确定miR- 125家族microrna在白血病前期状态和AML启动中的作用。在Specific Aim 2中，我们建议确定miR-125 microRNAs解除正常造血功能的细胞和分子机制。在Specific Aim 3中，我们将在小鼠模型和人类细胞中确定miR-125 microrna在维持白血病前期和白血病状况中的作用。总的来说，拟议的研究将通过具体解决miR- 125家族microRNAs在急性髓性白血病中的作用，促进我们对microRNAs在白血病起始和维持中的作用的理解。这项工作的成功将导致在小rna的基础上对一组流行的致命疾病的精确认识，并可能建立治疗干预的直接目标。

DESCRIPTION (provided by applicant): MicroRNAs are small non-coding RNAs that have recently become recognized as important molecular regulators in human cancer. However, despite the knowledge that microRNA expression is frequently deregulated in acute myeloid leukemia (AML), the role of microRNAs in the leukemic initiation and maintenance remains poorly understood, the understanding of which is our long-term goal. Following our previous work in trying to understand the role of microRNAs in hematopoiesis and in human cancers, here, we aim to understand the role of a specific microRNA family, the miR-125 family of microRNAs, in AML. We found that miR-125 family microRNAs display in vitro property associated with transformation in hematopoietic cells. Moreover, we have accumulated further evidence suggesting a role of these microRNAs in the leukemogenesis of AML. Through extensive microRNA expression profiling in human AMLs, we found a subgroup of AMLs display greatly elevated miR-125a or miR-125b levels. We also found that miR-125a expression is high in self-renewing hematopoietic stem cells (HSCs). Forced expression of miR-125a positively modifies stem cell activity and antagonizes the apoptotic pathway. In addition to our own work, it has been reported that miR-125b-1 is translocated in a subgroup of human AMLs and myelodysplastic syndromes. The major goal of this proposal is to determine the roles of miR-125 family microRNAs in leukemic initiation and maintenance, through developing and analyzing mouse models and human cells. In Specific Aim 1, we will use several mouse models to determine the role of miR- 125 family microRNAs in the initiation of pre-leukemic state and AML. In Specific Aim 2, we propose to identify the cellular and molecular mechanisms by which miR-125 microRNAs deregulate normal hematopoiesis. In Specific Aim 3, we will determine the role of miR-125 microRNAs in the maintenance of pre-leukemic and leukemic conditions in mouse models and in human cells. Collectively, the proposed research will advance our understanding of the role of microRNAs in leukemic initiation and maintenance by specifically addressing the role of miR- 125 family microRNAs in acute myeloid leukemia. Success of this work will lead to a refined appreciation of a group of prevalent fatal diseases on the basis of small RNAs, and could establish immediate targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Leukemia is one of the leading causes of cancer mortality. MicroRNAs, a type of small RNA molecules, have recently been identified and postulated as cellular regulators in leukemia. This proposal focuses on understanding the role of miRNAs in causing pre-leukemic disorders and leukemia, and in pre-leukemic and leukemic maintenance, which will lead to the appreciation of their potential as therapeutic targets.