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

项目摘要/摘要 多发性骨髓瘤(MM)是最常见的骨髓(BM)恶性肿瘤，目前仍无法治愈 绝大多数患者。已经知道宿主BM利基中的细胞对多发性骨髓瘤至关重要 生长以及MM和宿主BM微环境之间相互作用可以促进疾病的进展 以及故态复萌。目前新诊断的多发性骨髓瘤的治疗标准包括大剂量马法兰联合自体 干细胞移植后使用一种免疫调节药物进行长期维持治疗。而当 这些药物对MM细胞的影响已经得到了广泛的研究，细胞毒治疗对宿主的影响 BM的微环境仍然知之甚少。细胞减少、免疫麻痹与急性胰腺炎的发展 白血病是细胞毒治疗对宿主骨髓生态位造成的损害的不良后果，这种损害已经 已被报道，并对疾病进程产生重大影响。耐人寻味的是，最近的研究表明 细胞毒治疗对肿瘤周围微环境细胞的破坏导致 导致疾病复发的变化。鉴于MM细胞和宿主BM生态位之间的密切关系， 我们假设细胞毒治疗会导致宿主骨髓数量和质量的变化。 能促进MM生长和进展的微环境。为了解决这一假设，我们将调查 细胞毒治疗前、中和后宿主骨髓细胞生态位内细胞群体的转录变化 使用单细胞RNA测序技术(目标1)。细胞增殖、衰老和变异的分析 这些亚型中促癌途径的研究将揭开细胞毒素诱导的特定变化 心理治疗。此外，我们将确定细胞毒治疗如何改变免疫细胞的调节及其 与BM利基的其他细胞相互作用。Aim 2将研究复发患者的这些过程有何不同 早期(&lt；2年)和复发者(&gt；5年)。这些发现将确定这些免疫的作用 多发性骨髓瘤对免疫调节性药物治疗的反应。以确定细胞毒疗法是否- 诱导的伤害是可以克服的，我们将使用我们内部的SCID-Rab小鼠模型(目标3)。我们会调查的 抑制细胞毒治疗后升高的细胞因子转化生长因子-β的影响 并与肿瘤复发有关。这些研究的成功完成将提供一个 细胞毒治疗对骨髓微环境损伤的机制解释 MM旧病复发。这将允许开发更有效的治疗多发性骨髓瘤的方法，这是长期目标 这部作品的价值。

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.