Tumor Cell-Intrinsic/Extrinsic Mechanisms Underlying Myeloma Disease Progression

 描述（由申请方提供）：多发性骨髓瘤（MM）是一种无法治愈的克隆性浆细胞（PC）恶性肿瘤。MM的发展通常在无症状的前驱疾病之前，称为意义不明的单克隆丙种球蛋白病（MGUS）和郁积性骨髓瘤（SMM）。尽管这两种疾病的特征都是骨髓中异常但尚未癌变的克隆PC的积累（<10% bone marrow PCs in MGUS vs >在SMM中定义为10%），但这些患者中的许多人永远不会进展为MM，并且他们的克隆BMPC的频率多年来保持非常稳定。然而，所有MGUS和SMM患者均存在进展为MM的终生风险，其发生率分别为每年约1%和10%。由于恶性转化率低和目前治疗的毒性，MGUS或低风险SMM患者在不可逆终末器官损伤（例如，溶骨性疾病和肾功能不全）。在患者出现症状之前开始治疗显然是可取的，但目前尚不存在准确预测哪些患者将进展为恶性肿瘤并深入了解转化为MM的机制的特异性生物标志物。鉴于特定的三体性和染色体易位特征的MM PC已经存在于MGUS和SMM患者的克隆PC中，这些变化本身不是恶性肿瘤的原因。过去十年的纵向研究集中于确定恶性转化特征性的特定MM PC-内在基因组变化，但仅获得了少量成功，尽管已确定复发性突变，但患者间存在显著异质性，并且仍存在许多关于疾病进展的未回答问题。该建议的主要重点是在BM微环境（ME）的变化和先天性和适应性免疫细胞之间的关系，在接近异常BMPC的疾病进展过程中，从MGUS/SMM恶性MM。BMPC的免疫结构（原位免疫细胞的性质，密度，功能方向和空间关系）和它的潜在作用，在MGUS/SMM进展到MM以前没有研究。我们的具体假设是，BM ME积极抑制MGUS和SMM患者的疾病进展，ME的局灶性变化缓解了抑制，并允许这些修改的壁龛中的异常PC扩展。这些变化可能是由于PC龛内细胞的组成或功能因年龄而发生偏差，或者可能代表癌前细胞迁移到有利于疾病进展的龛内。我们还假设BM ME的变化实际上可能是由异常PC本身及其释放的微泡（MV）驱动的，这些微泡在区域上扩大了BMPC生态位并促进了全身性扩散。因此，该提案将重点关注MM进展期间BM ME中PC和MV驱动的免疫细胞改变、这些变化的功能后果以及与临床结局的相关性。

 DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable malignancy of clonal plasma cells (PC). The development of MM is typically preceded by asymptomatic precursor conditions termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Although both conditions are characterized by the accumulation of abnormal, but not yet cancerous, clonal PCs in the bone marrow (defined by <10% bone marrow PCs in MGUS vs >10% in SMM), many of these patients will never progress to MM and the frequency of their clonal BMPCs remains remarkably stable for years. However, all MGUS and SMM patients have a lifelong risk of progression to MM at a rate of ~1% and 10% per year, respectively. Because of the low transformation rate into malignancy and the toxicity of current treatments, no medical intervention is begun for MGUS or low risk SMM patients until after irreversible end-organ damage (e.g., lytic bone disease, and renal insufficiency) has occurred. It is clearly desirable to begin treatment before patients become symptomatic, but specific biomarkers that accurately predict which patients will progress to malignancy and also yield insight into the mechanisms responsible for transformation to MM do not currently exist. Given that specific trisomies and chromosomal translocations characteristic of MM PCs are already present in the clonal PCs in MGUS and SMM patients, these changes alone are not responsible for malignancy. Longitudinal studies over the past decade that have focused on identifying specific MM PC-intrinsic genomic changes that are characteristic of malignant transformation have been only marginally successful and although recurrent mutations have been identified, there is significant patient to patient heterogeneity and many unanswered questions concerning disease progression remain. The primary focus of this proposal is on changes in the BM microenvironment (ME) and the relationship between innate and adaptive immune cells in close proximity to abnormal BMPCs during disease progression from MGUS/SMM to malignant MM. The BMPC immune contexture (in situ immune cell nature, density, functional orientation, and spatial relationships) and its potential role in MGUS/SMM progression to MM have not been previously studied. Our specific hypothesis is that the BM ME actively suppresses disease progression in MGUS and SMM patients and that focal changes in the ME relieve the suppression and allow abnormal PCs in these modified niches to expand. These changes may be due to either deviations in the composition or function of the cells within the PC niche as a result of age, or may represent migration of the premalignant cells into a niche which is favorable to disease progression. We also hypothesize that changes to the BM ME may actually be driven by the abnormal PCs themselves and their release of microvesicles (MVs) that regionally expand the BMPC niche and facilitate systemic spread. This proposal will therefore focus on PC and MV-driven alterations of immune cells in the BM ME during MM progression, the functional consequences of these changes, and correlation with clinical outcome.