The role of miRNA15a and 16-1 in Multiple Myeloma

miRNA15a 和 16-1 在多发性骨髓瘤中的作用

• 批准号: 8490675
• 负责人: Irene M. Ghobrial
• 金额: $ 34.13万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490675
• 关键词: 13q14; Benign; Biology; Bone Marrow; Bone marrow biopsy; Bortezomib; Cells; Chromosomes; Clinical Trials; DLEU2 gene; Development; Dexamethasone; Differentiation and Growth; Disease; Disease Progression; Drug resistance; Epigenetic Process; Future; Gene Targeting; Genes; Grant; Growth; Hematologic Neoplasms; In Vitro; Knockout Mice; Lead; Malignant - descriptor; Malignant Neoplasms; Mesenchymal; Mesenchymal Differentiation; Mesenchymal Stem Cells; MicroRNAs; Molecular; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Neoplasm Metastasis; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Plasma Cells; Play; Prognostic Marker; Regulation; Regulator Genes; Research Personnel; Resistance; Role; Sampling; Serum; Staging; Stromal Cells; Therapeutic; Therapeutic Agents; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; base; in vivo; loss of function; mimetics; mouse model; pre-miRNA; prevent; prognostic; tumor; tumor growth; tumor progression

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.

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，且仍无法治愈，中位生存期为 3-5 年。 对于正常浆细胞中发生的导致增殖为恶性 MM 细胞的变化，一种可能的解释是表观遗传改变，例如 micro-RNA (miRNA) 的调节。 最近显示 miRNA 参与 MM 的发病机制。 在这笔资助中，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 的簇中，该簇在超过 50% 的 MM 患者中通常被删除。 我们最近发现 MM 细胞中 miR-15a 和 -16-1 的表达较低。 然而，目前缺乏的是对这些 miRNA 调节肿瘤进展和扩散的机制，以及这些 miRNA 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 通过 MM 克隆中发生的调节及其与 BM 微环境的相互作用，是 MM 中肿瘤进展和传播的关键调节因子。 在具体目标 1 中，我们将研究 miR-15a/-16-1 簇在疾病进展过程中作为 MM 克隆中的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 转基因小鼠模型和 DLEU2/miR15a/16-1 敲除小鼠进行。 在目标 2 中，我们将确定 miR-15-a/16-1 簇对 BM 环境中 MM 细胞和间充质细胞相互作用的作用。 在这里，我们将检查 MM 克隆与间充质干细胞/基质细胞的相互作用是否是通过外泌体中 miRNA 的转移。 最后，在目标 3 中，我们确定了 miR15a/16-1 对 MM 细胞传播和耐药性的作用。 在这里，我们将在体外和体内研究 miR15a/16-1 在调节 MM 细胞转移和侵袭中的作用。 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药物的敏感性/耐药性中的作用。 这些研究将导致 miR-15a/-16-1 作为临床实践中的预后标志物的应用。 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 治疗范式的转变，并可能允许基于特定 miRNA 表达的存在进行个体化治疗。 因此，该提议可能对 MM 患者具有重要的治疗和预后应用。