Therapy-induced Damage to the Host Bone Marrow as a Promoter of Treatment Resistance in Multiple Myeloma

项目概要/摘要 多发性骨髓瘤（MM）是骨髓（BM）最常见的恶性肿瘤，并且对于多发性骨髓瘤（MM）患者仍然是不可治愈的。 绝大多数患者。一段时间以来，人们已经知道，宿主BM龛中的细胞对MM至关重要 生长以及MM和宿主BM微环境之间的相互作用可以促进疾病进展 和复发新诊断MM的当前治疗标准包括高剂量美法仑与自体 干细胞移植后用免疫调节药物长期维持治疗。而 这些药物对MM细胞的作用已被广泛研究，细胞毒性治疗对宿主的作用 BM微环境仍然知之甚少。血细胞减少、免疫轻瘫和急性 白血病是细胞毒性治疗诱导的对宿主BM小生境的损害的不利后果， 已被报道，并对疾病进程产生重大影响。有趣的是，最近的研究表明， 细胞毒性治疗对肿瘤周围微环境细胞的损伤导致 这些改变会导致疾病复发。鉴于MM细胞与宿主BM小生境之间的密切关系， 我们假设细胞毒疗法导致宿主骨髓的定量和定性变化， 可以促进MM生长和进展的微环境。为了解决这一假设，我们将调查 在细胞毒性治疗之前、期间和之后，宿主BM小生境内细胞群的转录变化 使用单细胞RNA测序技术（Aim 1）。增殖、衰老和变异的分析 这些亚型中的促癌途径的研究将揭示细胞毒性T细胞诱导的特异性改变， 疗法此外，我们将确定细胞毒性疗法如何改变免疫细胞的调节， 与BM龛的其他细胞相互作用。目标2将研究这些过程在复发患者中的差异 早期（<2年）和复发晚期（>5年）。这些发现将确定这些免疫系统的作用。 对免疫调节药物治疗有反应的MM人群。为了确定细胞毒疗法- 为了克服诱导的损伤，我们将使用我们内部的SCID-rab小鼠模型（Aim 3）。我们将调查 抑制TGF-β的影响，TGF-β是一种细胞因子，已发现在细胞毒性治疗后患者中升高 并且与肿瘤复发有关。成功完成这些研究将提供一个 细胞毒性治疗诱导的BM微环境损伤如何促进 MM复发。这将允许开发更有效的MM疗法，这是长期目标。 这个工作。

PROJECT SUMMARY/ABSTRACT Multiple myeloma (MM) is the most common malignancy of the bone marrow (BM) and remains incurable for the vast majority of patients. It has been known for some time that cells in the host BM niche are crucial to MM growth and that interactions between MM and the host BM microenvironment can facilitate disease progression and relapse. Current treatment standards for newly diagnosed MM include high-dose melphalan with autologous stem cell transplantation followed by prolonged maintenance therapy with an immunomodulatory drug. While the effects of these agents on MM cells have been studied extensively, the effects of cytotoxic therapy on the host BM microenvironment remain poorly understood. Cytopenias, immunoparesis, and the development of acute leukemias are adverse consequences of cytotoxic therapy-induced damage to the host BM niche that have long been reported on and have a significant impact on the disease course. Intriguingly, recent research has shown that cytotoxic therapy-induced damage to the cells of the tumor-surrounding microenvironment leads to alterations that foster disease relapse. Given the intimate relationship between MM cells and the host BM niche, we hypothesize that cytotoxic therapy leads to quantitative and qualitative changes in the host BM microenvironment that can promote MM growth and progression. To address this hypothesis, we will investigate transcriptional changes in cell populations within the host BM niche before, during, and after cytotoxic therapy using single-cell RNA sequencing technology (Aim 1). The analysis of proliferation, senescence, and variation of cancer-promoting pathways within these subtypes will unravel the specific alterations induced by cytotoxic therapy. Furthermore, we will determine how cytotoxic therapy alters the regulation of immune cells and their interplay with other cells of the BM niche. Aim 2 will study how these processes differ in patients who relapse early (<2 years) and in those who relapse late (>5 years). The findings will identify the role of these immune populations in MM response to immunomodulatory drug therapy. To determine whether cytotoxic therapy- induced damage can be overcome, we will use our in-house SCID–rab mouse model (Aim 3). We will investigate the impact of inhibiting TGF-β, a cytokine that has been found to be elevated in patients after cytotoxic therapy and has been associated with tumor recurrence. Successful completion of these studies will provide a mechanistic explanation of how cytotoxic therapy-induced damage to the BM microenvironment can promote MM relapse. This will allow for the development of more effective therapies for MM, which is the long-term goal of this work.