The role of microRNAs in leukemic initiation and maintenance

描述（由申请人提供）：微小RNA是小的非编码RNA，其最近被认为是人类癌症中重要的分子调节剂。然而，尽管知道microRNA表达在急性髓细胞白血病（AML）中经常失调，但microRNA在白血病起始和维持中的作用仍然知之甚少，理解这一点是我们的长期目标。 在我们之前试图了解microRNA在造血和人类癌症中的作用的工作之后，在这里，我们的目标是了解特定microRNA家族，miR-125 microRNA家族在AML中的作用。我们发现miR-125家族microRNA在体外表现出与造血细胞转化相关的特性。此外，我们已经积累了进一步的证据，表明这些microRNA在AML的白血病发生中的作用。通过对人类AML中大量microRNA表达谱的分析，我们发现AML的一个亚组显示出显著升高的miR-125 a或miR-125 b水平。我们还发现miR-125 a在自我更新造血干细胞（HSC）中表达较高。miR-125 a的强制表达积极地改变干细胞活性并拮抗凋亡途径。除了我们自己的工作之外，有报道称miR-125 b-1在人类AML和骨髓增生异常综合征的一个亚组中发生易位。 该提案的主要目标是通过开发和分析小鼠模型和人类细胞来确定miR-125家族microRNA在白血病发生和维持中的作用。在具体目标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的启动中的作用。在具体目标2中，我们提出确定miR-125 microRNA失调正常造血的细胞和分子机制。在具体目标3中，我们将确定miR-125 microRNA在小鼠模型和人类细胞中维持白血病前和白血病状态中的作用。 总的来说，拟议的研究将通过专门解决miR- 125家族microRNA在急性髓性白血病中的作用，促进我们对microRNA在白血病启动和维持中的作用的理解。这项工作的成功将导致一组流行的致命疾病的小RNA的基础上的精细升值，并可以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.