The role of microRNAs in leukemic initiation and maintenance

描述(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，尽管知道在急性髓系白血病(AML)中，microRNA的表达经常被解除调控，但对于microRNA在白血病的启动和维持中的作用仍然知之甚少，了解这一点是我们的长期目标。继我们之前试图了解microRNAs在造血和人类癌症中的作用的工作之后，在这里，我们的目标是了解一个特定的microRNA家族-miR-125家族在AML中的作用。我们发现miR-125家族microRNAs在体外表现出与造血细胞转化相关的特性。此外，我们还积累了进一步的证据，表明这些microRNAs在AML的白血病发生中发挥了作用。通过在人类AML中广泛的microRNA表达谱，我们发现AML的一个亚组表现出显著的miR-125a或miR-125b水平升高。我们还发现miR-125a在自我更新的造血干细胞(HSCs)中高表达。强制表达miR-125a可积极改变干细胞活性，并拮抗凋亡途径。除了我们自己的工作，已经有报道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。这项建议的主要目标是通过建立和分析小鼠模型和人类细胞来确定miR-125家族microRNAs在白血病启动和维持中的作用。在具体目标1中，我们将使用几个小鼠模型来确定miR-125家族microRNAs在白血病前期状态和AML启动中的作用。在特定的目标2中，我们建议确定miR-125microRNAs解除正常造血调控的细胞和分子机制。在具体目标3中，我们将确定miR-125microRNAs在维持小鼠模型和人类细胞中白血病前期和白血病条件中的作用。总之，这项拟议的研究将通过具体阐述miR-125家族microRNAs在急性髓系白血病中的作用，促进我们对microRNAs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在小RNA的基础上对一组流行的致命疾病进行精细的评估，并可能为治疗干预建立直接的目标。

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.