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

• 批准号: 10350595
• 负责人: Michael Edward Vinyard
• 金额: $ 4.68万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 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/10350595
• 关键词: Acute Myelocytic Leukemia; 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; Hematology; 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; Proteins; Publishing; Regulation; Regulatory Element; Research; Resolution; Role; Sampling; Supervision; Susceptibility Gene; System; Techniques; Testing; Therapeutic Intervention; Tissues; Work; acute myeloid leukemia cell; 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; novel; patient subsets; prevent; rate of change; reconstruction; relating to nervous system; single-cell RNA sequencing; transcription factor; transcriptomics; tumor

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。 MM前面有一个较少的生命- 威胁血液状况，与多发性骨髓瘤类似，但不致命且无症状2。事实上，大多数人并不 甚至知道他们拥有它。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患有多发性骨髓瘤 前兆条件继续发展为完整的疾病，以及为什么其他人不会。这个问题已经被处理过 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。 前兆条件和谁没有。骨髓创造一个支持血液发育的微环境 细胞。多发性骨髓瘤劫持骨髓微环境（BMM）以有利于自身生长3。没有一个 癌症发展的遗传驱动因素，我假设 BMM 经过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。 表达给定的基因。 CR 通过修改基因周围的组蛋白来执行此过程 被包裹（组蛋白和 DNA 一起构成染色质，因此：染色质调节剂）。此外 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 上调或下调基因的表达水平。一种特定的 CR LSD1，已知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 另一种蛋白质。当这种相互作用被破坏时，主转录因子能够开启基因，导致 AML 细胞 死5。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增强了 MM6的成长。有趣的是，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。虽然这些突变仅占 MM 病例的一小部分，但这表明 LSD1 是一种 MM7 开发的关键组成部分。因此我推测 LSD1 在 毫米;该角色可能是 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。