Molecular Manipulation to Enhance Anti-Myeloma Response

分子操作增强抗骨髓瘤反应

• 批准号: 10486218
• 负责人: Nikhil C. Munshi
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486218
• 关键词: Affect; African American population; Age; Anabolism; Area; Automobile Driving; Biological; CRISPR interference; Caucasians; Cell Line; Cell Survival; Cells; Chromosomes; Classification; Clinical; DNA; Data; Data Set; Dependence; Development; Diagnosis; Disease; Enzymes; Evaluation; Fatty Acids; Genes; Genomic Instability; Genomics; Glucose; Glutamine; Growth; Human Genome; Impairment; In Vitro; Incidence; Investigation; Lead; Left; Malignant Neoplasms; Membrane; Metabolic Pathway; Modeling; Molecular; Multiple Myeloma; Mutation; Names; Newly Diagnosed; Nutrient; Oligonucleotides; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Plasma Cells; Play; Probability; Proteins; RNA; Records; Regulatory Element; Relapse; Reporting; Research; Risk; Risk Marker; Role; Sampling; Signaling Molecule; Silicon Dioxide; Span 80; Stem cell transplant; Subgroup; Techniques; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Transgenic Organisms; Untranslated RNA; Up-Regulation; Validation; Veterans; agent orange; c-myc Genes; cell growth; chemotherapy; comorbidity; differential expression; experimental study; genetic manipulation; high risk; improved; in vivo; inhibitor; lipid biosynthesis; molecular marker; mouse model; neoplastic cell; novel; outcome prediction; patient stratification; patient subsets; predict clinical outcome; progression marker; protein protein interaction; response; small molecule; small molecule inhibitor; survival outcome; therapeutic target; transcriptome sequencing; transcriptomics; translational applications; translational therapeutics

Multiple myeloma (MM) is a heterogenous disease. Although there have been several novel agents and combinations available for treatment, the genomic adaptability of the tumor cells lead to their continued growth and and adverse survival outcome. Therefore there is need for identification of novel target sand directed therapies. One of the emrging areas of research in this direction has been the recent advances highlighting the functional significance of long noncoding RNAs (lncRNAs) that span > 80% of human genome. These RNA molecules control variety of cellular and molecular functions via mechanisms that are as yet not well described. In our preliminary investigation we utilized our RNA- seq data from CD138+ MM cells from 308 newly diagnosed and uniformly treated patients, and 16 normal plasma cells and described the aberrant lncRNA landscape in MM. We identified 869 differentially expressed lncRNAs in MM compared to normal plasma cells. We identified 14 lncRNAs associated with PFS and calculated a risk score that stratified patients and report their significant role as an independent risk predictor for clinical outcome1. These results provided the rationale to further investigate biological and molecular activity of lncRNA in MM. We evaluated 913 expressed lncRNAs for impact on MM cell viability in a preliminary CRISPR interference (CRISPRi)-based screen. A primary screen in 3 MM cell lines identified 20 lncRNAs impacting MM cell viability. Evaluation using RNA-seq data showed a significant upregulation of these 20 lncRNAs. Of note, specific lncRNAs were found selectively upregulated in genetically-defined patient subsets, including high-risk MM carrying t(4;14). A secondary screen (of the most enriched or depleted sgRNAs) identified MIR17HG (RNA Regulator of Lipogenesis; RROL), as one of the top hits as a novel lncRNA in MM. In subsequent experiments, suppression of RROL significantly impaired MM cell growth and survival in vitro and in vivo. We also observed that Acetyl Co-A Carboxylase 1 (ACC1), the rate-limiting enzyme of de novo lipogenesis (DNL) pathway, is one of the primary targets of RROL. This metabolic pathway converts nutrients (glucose, glutamine, etc.) into fatty acids serving for energy storage or biosynthesis of membranes and signaling molecules. We have also begun to investigate inhibitors of both lncRNA RROL as well as ACC1 and observed anti-MM activity. Based on these observations, we hypothesize that dysregulated lncRNAs significantly impact the pathobiology of MM by their ability to control multiple genes, with potential to serve as therapeutic targets. To further understand the role of lncRNAs in MM and identify those associated with progression, and to evaluate their therapeutic potential, we will identify functional lncRNA dependencies in myeloma (Aim 1), validate the role of functional lncRNAs in MM (Aim 2) and evaluate inhibitors of MIR17HG (RROL) and its downstream target using small molecule and transgenic manipulations in MM (Aim 3). These studies will define the unique functional landscape of lncRNA in MM and allow development of translational applications.

多发性骨髓瘤（MM）是一种异质性疾病。尽管已经有几种新的药物 和可用于治疗的组合，肿瘤细胞的基因组适应性导致其 持续生长和不良生存结局。因此，有必要对新的 靶向沙导向疗法。在这个方向上的一个新兴的研究领域是 最近的进展突出了长非编码RNA（lncRNA）的功能意义， 超过80%的人类基因组。这些RNA分子通过调控细胞和分子的各种功能， 这些机制尚未得到很好的描述。在我们的初步调查中，我们使用了我们的RNA- 来自308名新诊断和统一治疗患者的CD 138 + MM细胞的seq数据，以及16名 正常浆细胞，并描述了异常lncRNA景观在MM。我们确定了869 与正常浆细胞相比，MM中差异表达的lncRNA。我们鉴定了14种lncRNAs 与PFS相关，并计算风险评分，对患者进行分层，并报告其显著作用 作为临床结果的独立风险预测因子1。这些结果为进一步研究提供了依据。 研究了MM中lncRNA生物学和分子生物学活性，我们评估了913个表达的lncRNA 在初步的基于CRISPR干扰（CRISPRi）的筛选中对MM细胞活力的影响。主 在3个MM细胞系中的筛选鉴定了20种影响MM细胞活力的lncRNA。使用RNA-seq进行评估 数据显示这20种lncRNA的显著上调。值得注意的是，我们发现了 在遗传学定义的患者亚群中选择性上调，包括携带t（4;14）的高危MM。 （最富集或耗尽的sgRNA的）二次筛选鉴定了MIR 17 HG（RNA调节子）。 脂肪生成; RROL），作为MM中新型lncRNA的热门之一。在随后的实验中， 抑制RROL在体外和体内显著损害MM细胞生长和存活。我们也 观察到乙酰辅酶A羧化酶1（ACC 1），从头脂肪生成的限速酶， (DNL)是RROL的主要靶点之一。这种代谢途径将营养物质 （葡萄糖、谷氨酰胺等）转化为脂肪酸，用于能量储存或膜的生物合成， 信号分子我们还开始研究lncRNA RROL以及 ACC 1和观察到的抗MM活性。基于这些观察，我们假设， lncRNA通过其控制多个基因的能力显著影响MM的病理生物学， 作为治疗靶点的潜力。为了进一步了解lncRNA在MM中的作用， 这些与进展相关，并评估其治疗潜力，我们将确定功能性 骨髓瘤中的lncRNA依赖性（目的1），验证功能性lncRNA在MM中的作用（目的2）， 使用小分子和转基因技术评估MIR 17 HG（RROL）及其下游靶标的抑制剂 MM中的操作（目标3）。这些研究将确定lncRNA在人类免疫系统中的独特功能。 MM，并允许开发翻译应用程序。

项目成果

Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma.

• DOI: 10.1038/leu.2015.228
• 发表时间: 2016-02
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Prabhala RH;Fulciniti M;Pelluru D;Rashid N;Nigroiu A;Nanjappa P;Pai C;Lee S;Prabhala NS;Bandi RL;Smith R;Lazo-Kallanian SB;Valet S;Raje N;Gold JS;Richardson PG;Daley JF;Anderson KC;Ettenberg SA;Di Padova F;Munshi NC
• 通讯作者: Munshi NC

Dual PAK4-NAMPT Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in Waldenström Macroglobulinemia.

• DOI: 10.1158/1078-0432.ccr-18-1776
• 发表时间: 2019-01-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Li N;Lopez MA;Linares M;Kumar S;Oliva S;Martinez-Lopez J;Xu L;Xu Y;Perini T;Senapedis W;Baloglu E;Shammas MA;Hunter Z;Anderson KC;Treon SP;Munshi NC;Fulciniti M
• 通讯作者: Fulciniti M

Risk factors in multiple myeloma: is it time for a revision?

• DOI: 10.1182/blood.2019004309
• 发表时间: 2021-01-07
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Corre, Jill;Munshi, Nikhil C.;Avet-Loiseau, Herve
• 通讯作者: Avet-Loiseau, Herve

RAD51 Inhibitor Reverses Etoposide-Induced Genomic Toxicity and Instability in Esophageal Adenocarcinoma Cells.

• DOI: 10.46439/toxicology.2.006
• 发表时间: 2020
• 期刊: Archives of clinical toxicology
• 作者: Liao C;Zhao J;Kumar S;Chakraborty C;Talluri S;Munshi NC;Shammas MA
• 通讯作者: Shammas MA

Integrated genomics and comprehensive validation reveal drivers of genomic evolution in esophageal adenocarcinoma.

• DOI: 10.1038/s42003-021-02125-x
• 发表时间: 2021-05-24
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Kumar S;Buon L;Talluri S;Roncador M;Liao C;Zhao J;Shi J;Chakraborty C;Gonzalez G;Tai YT;Prabhala R;Samur MK;Munshi NC;Shammas MA
• 通讯作者: Shammas MA