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

项目总结/摘要 多发性骨髓瘤（MM）每年在美国造成近13，000人死亡1。MM之前是少生- 威胁性血液病，类似于MM，但非致命且无症状2。事实上，大多数人不知道 MM研究中一个突出的问题是，为什么一些被诊断患有MM的患者， 前驱条件继续发展的完整的疾病，为什么其他人没有。这个问题已经被讨论过了， 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一个 前体条件和谁没有。骨髓创造了一个微环境来支持血液的发育 细胞多发性骨髓瘤劫持骨髓微环境（BMM）以促进自身生长3。没有 癌症发展的遗传驱动因素，我假设BMM是表观遗传修饰，以促进 MM的选择性生长 表观遗传学包括影响基因表达而不改变基因本身的遗传学。 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， 表达特定的基因。CRs通过修饰基因周围的组蛋白来完成这一过程， 被包裹（组蛋白和DNA一起构成染色质，因此：染色质调节子）。除了 除了这些非常特殊的功能外，CRs还可以介导与转录因子（TF）的相互作用， 上调或下调基因的表达水平一种特定的CR LSD 1，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LSD 1活性的药物非常有效 急性髓性白血病（AML）45.这些药物通过破坏LSD 1和LSD 2之间的相互作用来发挥作用。 另一种蛋白质当这种相互作用被破坏时，主TF能够打开导致AML细胞增殖的基因。 死5.尽管AML和MM之间存在一些相似之处，但使用LSD 1靶向药物治疗实际上可以增强AML和MM的免疫反应。 MM 6的成长有趣的是，已经发现一小部分患者易患MM 通过LSD 1中的一组可遗传突变来发展-这些突变模拟赋予药物 AML耐药5，6.虽然这些突变只占MM病例的一小部分，但它指出LSD 1是MM的一部分。 MM 7开发中的关键组件。因此，我假设LSD 1在以下过程中发挥作用： MM;此角色可能特定于BMM。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， 关于驱动BMM促进MM进展的因素。 2.从各种MM发展的患者中收集BMM样本，以分析单细胞基因 表达和染色质可及性数据，以了解表观基因组被改变为MM的方式 在BMM中取得进展。

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.