The role of miRNA15a and 16-1 in Multiple Myeloma

描述（由申请人提供）：多发性骨髓瘤（MM）是第二常见的血液恶性肿瘤，它仍然是无法治愈的，中位生存期为3-5年。对于正常浆细胞中发生的导致恶性MM细胞增殖的变化，一种可能的解释是表观遗传改变，如微rna （miRNAs）的调节。mirna最近被证明参与MM的发病机制。在本研究中，我们选择关注miR-15a和-16-1在MM进展中的作用。miR-15a和-16-1存在于位于染色体13q14的一个簇中，超过50%的MM患者通常缺失。我们最近发现miR-15a和-16-1在MM细胞中的表达较低。然而，目前缺乏的是对这些miRNAs调节肿瘤进展和传播的机制，以及这些miRNAs如何调节肿瘤克隆与BM微环境之间的相互作用的更好理解。我们假设miR-15a和-16-1是MM中肿瘤进展和传播的关键调节因子，通过MM克隆及其与BM微环境的相互作用进行调节。在Specific aim 1中，我们将研究miR-15a/-16-1簇在MM克隆疾病进展过程中作为肿瘤抑制因子的作用。这将使用MM进展期间患者的样本，以及MM和deleu2 /miR15a/16-1敲除小鼠的转基因小鼠模型来进行。在Aim 2中，我们将确定miR-15-a/16-1簇在BM环境中MM细胞和间充质细胞相互作用中的作用。在这里，我们将研究MM克隆与间充质干细胞/基质细胞的相互作用是否通过外泌体中miRNA的转移。最后，在Aim 3中，我们确定了miR15a/16-1在MM细胞播散和耐药中的作用。在这里，我们将在体外和体内研究miR15a/16-1在MM细胞转移和侵袭调控中的作用。我们还将确定miR15a/16-1在调节MM细胞对硼替佐米和地塞米松等治疗剂的敏感性/耐药性中的作用。这些研究将促使miR-15a/-16-1作为临床实际应用的预后标志物。此外，可用于患者临床试验的pre-miRNA模拟物的开发可能会导致MM治疗的范式转变，并可能基于特定miRNA表达的存在进行个体化治疗。因此，该建议可能对MM患者具有重要的治疗和预后应用。

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is the second most prevalent hematological malignancy and it remains incurable, with a median survival of 3-5 years. One possible explanation for the changes that occur in normal plasma cells that lead to proliferation into malignant MM cells is epigenetic alterations, such as the regulation of micro-RNA (miRNAs). miRNAs have recently been shown to be involved in the pathogenesis of MM. In this grant, we chose to focus on the role of miR-15a and -16-1 in the progression of MM. miR-15a and -16-1 are present in a cluster located at chromosome 13q14, which is commonly deleted in over 50% of patients with MM. We have recently shown that the expression of miR-15a and -16-1 is low in MM cells. However, what is lacking is a better understanding of the mechanisms by which these miRNAs regulate tumor progression and dissemination, and how these miRNAs regulate interactions between the tumor clone and the BM microenvironment. We hypothesize that miR-15a and -16-1 are critical regulators of tumor progression and dissemination in MM, through regulations that occur in the MM clone and its interaction with the BM microenvironment. In Specific aim 1, we will examine the role of the miR-15a/-16-1 cluster as tumor suppressors in the MM clone during disease progression. This will be performed using samples from patients during MM progression, and through transgenic mouse models of MM and DLEU2/miR15a/16-1 knockout mice. In Aim 2, we will determine the role of the miR-15-a/16-1 cluster on the interaction of MM cells and mesenchymal cells in the BM milieu. Here, we will examine whether the interaction of the MM clone and the mesenchymal stem cells/stromal cells is through transfer of miRNA in exosomes. Finally, in Aim 3, we determine the role of miR15a/16-1 on cell dissemination and drug-resistance in MM. Here, we will examine the role of miR15a/16-1 in the regulation of cell metastasis and invasion in MM in vitro and in vivo. We will also determine the role of miR15a/16-1 in regulating sensitivity/resistance of MM cells to therapeutic agents such as bortezomib and dexamethasone. These studies will lead to the application of miR-15a/-16-1 as prognostic markers clinically used in practice. In addition, the development of pre-miRNA mimetics that can be used in clinical trials for patients may lead to a paradigm shift in the treatment of MM, and may allow individualized therapy based on the presence of specific miRNA expression. Therefore, this proposal will likely have significant therapeutic and prognostic applications for patients with MM.