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

项目摘要/摘要 在美国，多发性骨髓瘤(MM)每年导致近13,000人死亡。在MM之前有一个较少的生活- 威胁血液状况，类似于MM，但不致命且无症状2。事实上，大多数人并不这样认为 甚至知道他们有这种病。多发性骨髓瘤研究中的一个悬而未决的问题是，为什么一些被诊断为 前驱症状会继续发展为全身性疾病，为什么其他人不会。这个问题已经被探讨过了 然而，从遗传学的角度来看，并没有明确的遗传联系来定义谁会从一个 前驱状态和谁不是。骨髓创造支持血液发育的微环境 细胞。多发性骨髓瘤劫持了骨髓微环境(BMM)，以利于自身的生长。如果没有 癌症发生的基因驱动因素，我假设BMM在表观遗传上被修改，以促进 选择生长MM。 表观遗传学包括那些在不改变基因本身的情况下影响基因表达的东西。 染色质调节剂(CRS)是一种通过改变细胞的能力来调节表观遗传变化的蛋白质 表达一种特定的基因。CRS通过修改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，因此称为染色质调节剂)。除了……之外 这些非常特殊的功能，CRS还可以调节与转录因子(TF)的相互作用，这些蛋白质 调高或调低基因表达水平。一种特定的CRLSD1，已知可以抑制或关闭基因， 一直是其他血癌疾病的靶点，旨在阻断LSD1活性的药物相当有效 在急性髓系白血病(AML)模型中45。这些药物通过破坏LSD1和LSD1之间的相互作用而起作用 另一种蛋白质。当这种相互作用被破坏时，主转移因子能够启动导致AML细胞 死亡5。尽管AML和MM之间有一些相似之处，但LSD1靶向药物的治疗实际上增强了 MM6的成长。有趣的是，有一小部分患者被发现易患多发性骨髓瘤 通过LSD1的一组可遗传突变发展--这些突变模仿赋予药物的突变 虽然这些突变只占MM病例的一小部分，但它表明LSD1是一种 MM7开发中的关键组件。因此，我假设LSD1在骨肉瘤的进展中起作用。 嗯；这个角色可能是BMM特有的。这一项目的具体目标可以概括如下： 1.开发使用机器学习和数学学习的新技术的计算工具 关于推动BMM对MM的进展做出贡献的因素。 2.收集不同多发性骨髓瘤患者的骨髓瘤样本，以分析单细胞基因 表达和染色质可及性数据，以了解表观基因组改变为MM的方式 在BMM方面取得了进展。

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.