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: 8187715
• 负责人: Irene M. Ghobrial
• 金额: $ 36.31万
• 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/8187715
• 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. PUBLIC HEALTH RELEVANCE: Multiple Myeloma (MM) is the second most prevalent hematological malignancy and it remains incurable with a median survival of 3-5 years. In many cases, MM progresses from a more benign-like stage of monoclonal gammopathy of undetermined significance (MGUS). This grant focuses on understanding the role of specific regulators of genes called miRNA. We will examine the role of two miRNAs, miR15a and 16-1 in the regulation of progression and dissemination in MM. New drugs are being developed to target these miRNAs. These new drugs will lead to a paradigm shift in the treatment of MM, where we could prevent disease progression to active MM, or revert MM to an MGUS-like stage.

描述（由申请人提供）：多发性骨髓瘤（MM）是第二个流行的血液系统恶性肿瘤，并且仍然无法治愈，中位生存期为3 - 5年。 对于正常浆细胞中导致恶性MM细胞增殖的变化的一种可能解释是表观遗传学改变，例如微-RNA的调节（miRNA）。 最近已显示miRNA参与MM的发病机理。 在这笔赠款中，我们选择着重于miR-15a和-16-1在MM进展中的作用。 MiR-15a和-16-1存在于13q14染色体的簇中，通常在50％以上的MM患者中删除。 我们最近表明，mM-15a和-16-1的表达在MM细胞中较低。 但是，缺乏的是对这些miRNA调节肿瘤进展和传播的机制的更好理解，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。 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剂。 在特定的目标1中，我们将检查miR-15a/-16-1簇作为疾病进展过程中MM克隆中肿瘤抑制剂的作用。 这将在MM进展过程中使用患者的样品以及MM和DLEU2/MIR15A/16-1敲除小鼠的转基因小鼠模型进行。 在AIM 2中，我们将确定miR-15-A/16-1簇在BM Milieu中MM细胞和间充质细胞相互作用中的作用。 在这里，我们将检查MM克隆和间充质干细胞/基质细胞的相互作用是否是通过在外泌体中的miRNA转移。 最后，在AIM 3中，我们确定了miR15a/16-1对MM中细胞传播和耐药性的作用。 在这里，我们将研究miR15a/16-1在体外和体内MM中的细胞转移和侵袭中的作用。 我们还将确定miR15a/16-1在调节MM细胞对治疗剂（如硼替努比和地塞米松）中的敏感性/耐药性中的作用。 这些研究将导致将miR-15a/-16-1应用于实践中临床使用的预后标记。 此外，可以在患者临床试验中使用的MIRNA前模拟物的发展可能会导致MM治疗的范式转移，并且可以基于特定miRNA表达的存在允许个性化治疗。 因此，该提案可能对MM患者具有明显的治疗和预后应用。 公共卫生相关性：多发性骨髓瘤（MM）是第二大流行的血液系统恶性肿瘤，并且中位生存期3 - 5年仍然无法治愈。 在许多情况下，MM从不确定意义（MGU）的单克隆性γ-肾上腺病的良性样阶段发展。 该赠款专注于理解称为miRNA的基因特定调节因子的作用。 我们将研究两个miRNA，miR15a和16-1在MM中的进展和传播中的作用。 正在开发新药以瞄准这些miRNA。 这些新药将导致MM治疗的范式转移，我们可以防止疾病发展为活性MM，或将MM恢复到MGUS样阶段。