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: 10154128
• 负责人: Michael Edward Vinyard
• 金额: $ 4.6万
• 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/10154128
• 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; Pharmaceutical Preparations; Plasma Cells; Plasma Enhancement; Play; Precancerous Conditions; Process; Proteins; Publishing; Regulation; Regulator Genes; 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; 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.

项目摘要 /摘要 在美国，多发性骨髓瘤（MM）每年杀死近13,000人。 MM之前是寿命较少 - 威胁血液状况，类似于MM，但无症状和无症状2。实际上，大多数人都不 甚至知道他们有。 MM研究中的一个杰出问题是，为什么一些被诊断为患有的患者 前体的状况继续发展出全部疾病，以及为什么其他人不这样做。这个问题已经解决 从遗传学的角度来看，没有明确的遗传联系定义谁继续从一个 前体状况，谁没有。骨髓创造了一个微环境，以支持流血 细胞。多发性骨髓瘤劫持了骨髓微环境（BMM）以偏爱自己的生长3。没有一个 癌症发展的遗传驱动力，我假设BMM是表观遗传的，以促进 MM的选择性增长。 表观遗传学包括影响基因表达而不会改变基因本身的表达。 染色质调节剂（CRS）是蛋白质，通过改变细胞的能力来介导表观遗传变化 表达给定的基因。 CRS通过修改围绕基因的Hisstone蛋白来执行此过程 被包裹（组蛋白和DNA结合在一起，包括染色质，因此：染色质调节剂）。此外 这些非常具体的功能，CRS还可以介导转录因子（TFS）的相互作用，即蛋白质 将基因的表达水平上升或向下。特定的Cr LSD1，已知可以反映或关闭基因， 一直是其他血癌疾病和旨在阻止LSD1活性的药物的靶标 在急性髓样白血病（AML）的模型中45。这些药物通过破坏LSD1和 另一种蛋白质。当这种相互作用破坏时，主TF能够打开导致AML细胞的基因 死亡5。尽管AML和MM之间有一些相似之处，但使用LSD1靶向药物的治疗实际上增强了 MM6的生长。有趣的是，已经发现一小部分患者易于MM 通过LSD1中的一组可遗传的突变开发 - 这些突变模仿了会召集药物的突变 AML5,6的阻力。尽管这些突变仅占MM病例的一小部分，但它指的是LSD1 MM7开发的关键组成部分。因此，我假设LSD1在 毫米;该角色可能针对BMM。该项目的具体目的可以总结如下： 1。使用机器学习和数学的新技术开发计算工具 关于驱动BMM的因素有助于MM的进展。 2。从MM发育范围的患者那里收集BMM样品，以分析单细胞基因 表达和染色质可访问性数据，以学习为MM改变表观基因组的方式 在BMM中进展。