Determining the role of LSD1 in multiple myeloma through a multi-omics approach at single cell resolution

通过单细胞分辨率的多组学方法确定 LSD1 在多发性骨髓瘤中的作用

基本信息

批准号：
10547824
负责人：
Michael Edward Vinyard
金额：
$ 4.25万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-04 至 2026-01-03
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10547824
关键词：
Acute Myelocytic Leukemia Address Architecture Automobile Driving Blood Blood Cells Bone Marrow Cell Differentiation process Cells Cellular biology Chromatin Clinical Trials Clonal Expansion Collaborations Computing Methodologies DNA Data Development Diagnosis Differential Equation Dimensions Disease Disease Progression Doctor of Philosophy Drug Design Drug Targeting Drug resistance Epigenetic Process Equation Event Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Heterogeneity Genomics Growth Hematologic Neoplasms Hematopoietic Neoplasms Heritability Histones Investigation KDM1A gene Learning Life Link Lysine Machine Learning Malignant - descriptor Malignant Neoplasms Mathematics Mediating Methods Modeling Multiple Myeloma Mutation Neoplasms Oncogenes Oncogenic Patients Persons Pharmaceutical Preparations Plasma Cells Plasma Enhancement Play Precancerous Conditions Process Proliferating Proteins Publishing Regulation Regulatory Element Repression Research Resolution Role Sampling Shapes Susceptibility Gene System Techniques Testing Therapeutic Intervention Tissues Tumor Suppressor Proteins United States Visualization Work acute myeloid leukemia cell autosome bone cell cell growth cohort comparative computer framework computerized tools disorder prevention epigenome epigenomics experimental study gene regulatory network high dimensionality improved insight machine learning method multiple omics neural novel patient subsets prevent rate of change reconstruction single-cell RNA sequencing transcription factor transcriptomics

项目摘要

PROJECT SUMMARY / ABSTRACT Multiple myeloma (MM) kills nearly 13,000 people annually in the United States1. MM is preceded by a less life- threating blood condition, which is similar to MM, yet non-lethal and asymptomatic2. in fact, most people don’t even know they have it. An outstanding question in MM research is why some patients diagnosed with the precursor condition go on to develop the full disease and why others do not. This question has been approached from a genetics standpoint, however there is no clear genetic link defining who goes on to develop MM from a precursor condition and who does not. Bone marrow creates a microenvironment to support developing blood cells. Multiple myeloma hijacks the bone marrow microenvironment (BMM) to favor its own growth3. Without a genetic driver of cancer development, I hypothesize that the BMM is modified epigenetically to facilitate the selective growth of MM. Epigenetics encompasses that which influences the expression of genes without altering the genes themselves. Chromatin regulators (CRs) are proteins that mediate epigenetic changes through altering the ability of a cell to express a given gene. CRs carry out this process through modifying the histone proteins around which genes are wrapped (histones and DNA taken together comprise chromatin, hence: chromatin regulators). In addition to these very specific functions, CRs can also mediate interactions with transcription factors (TFs), the proteins that turn the expression levels of genes up or down. A specific CR LSD1, which is known to repress or turn off genes, has been the target of other blood cancer diseases and drugs designed to block LSD1 activity are quite effective in models of acute myeloid leukemia (AML)45. These drugs work by disrupting an interaction between LSD1 and another protein. When that interaction is disrupted, a master TF is able to turn on genes that cause AML cells to die5. Despite some similarities between AML and MM, treatment with LSD1-targeting drugs actually enhances the growth of MM6. Interestingly, a small subset of patients have been found to be predisposed to MM development through a heritable set of mutations in LSD1 – these mutations mimic mutations that confer drug resistance in AML5,6. While these mutations only make up a small fraction of MM cases, it points to LSD1 as a key component in the development of MM7. I thereby hypothesize that LSD1 plays a role in the progression of MM; this role is potentially specific to the BMM. The specific aims of this project can be summarized as follows: 1. Develop a computational tool using novel techniques from machine learning and mathematics to learn about factors that drive the BMM to contribute to the progression of MM. 2. Collect BMM samples from patients across a spectrum of MM development to analyze single cell gene expression and chromatin accessibility data to learn the ways in which the epigenome is altered as MM progresses in the BMM.

项目概要/摘要在美国，多发性骨髓瘤 (MM) 每年导致近 13,000 人死亡1。威胁性血液状况，与多发性骨髓瘤类似，但实际上大多数人并不致命且无症状2。多发性骨髓瘤研究中的一个突出问题是为什么有些患者被诊断出患有这种疾病。前兆条件继续发展为完整的疾病，为什么其他人没有这个问题已经被解决。然而，从遗传学的角度来看，没有明确的遗传联系来定义谁会从 MM 发展为 MM。骨髓创造了支持血液发育的微环境。多发性骨髓瘤劫持骨髓微环境（BMM）以利于其自身生长3。癌症发展的遗传驱动因素，我帮助对 BMM 进行了表观遗传修饰，以促进 MM的选择性生长。表观遗传学涵盖影响基因表达而不改变基因本身的因素。染色质调节因子 (CR) 是通过改变细胞的能力来介导表观遗传变化的蛋白质。 CR 表达特定基因，通过修饰基因周围的组蛋白来实现这一过程。被包裹（组蛋白和 DNA 一起构成染色质，因此：染色质调节剂）。这些非常特殊的功能，CR 还可以介导与转录因子 (TF) 的相互作用，转录因子是提高或降低基因的表达水平，已知它可以抑制或关闭基因，一直是其他血癌疾病的目标，旨在阻断 LSD1 活性的药物非常有效在急性髓系白血病 (AML) 模型中45，这些药物通过破坏 LSD1 和 LSD1 之间的相互作用发挥作用。当这种相互作用被破坏时，主 TF 能够启动导致 AML 细胞发生变化的基因。尽管 AML 和 MM 之间存在一些相似之处，但 LSD1 靶向药物的治疗实际上可以增强疗效。 MM6 的生长表明，一小部分患者被发现易患 MM。通过 LSD1 的一组可遗传突变进行发育——这些突变模仿赋予药物的突变 AML5,6 中的耐药性虽然这些突变只占 MM 病例的一小部分，但它表明 LSD1 是一种耐药性。因此，我发现 LSD1 在 MM7 的发展中发挥着重要作用。 MM；这个角色可能是 BMM 特有的。该项目的具体目标可概括如下： 1. 使用机器学习和数学的新技术开发计算工具来学习关于驱动 BMM 促进 MM 进展的因素。 2. 从一系列 MM 发育过程中收集患者的 BMM 样本，以分析单细胞基因表达和染色质可及性数据，以了解表观基因组作为 MM 的改变方式 BMM 取得进展。