Tumor Cell-Intrinsic/Extrinsic Mechanisms Underlying Myeloma Disease Progression

 描述(申请人提供)：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。多发性骨髓瘤的发展通常先于无症状的前驱症状，称为未确定意义的单克隆性伽马病(MGUS)和阴燃骨髓瘤(SMM)。虽然这两种情况的特点都是异常的，但尚未癌变的克隆性PC在骨髓中堆积(定义为MGUS中10%的骨髓PC与SMM中10%的骨髓PC)，其中许多患者永远不会进展为MM，其克隆性BMPC的频率多年来保持显著稳定。然而，所有MGUS和SMM患者都有终身进展为MM的风险，分别为每年约1%和10%。由于MGUS或低风险SMM患者的恶性转化率较低，且现有治疗方法的毒性较大，因此在发生不可逆性终末器官损害(如溶骨病和肾功能不全)之前，不会开始对MGUS或低风险SMM患者进行治疗。在患者出现症状之前开始治疗显然是可取的，但目前还不存在准确预测哪些患者将进展为恶性肿瘤的特定生物标志物，以及对转化为MM的机制的洞察。鉴于在MGUS和SMM患者的克隆性PC中已经存在MM PC的特殊三体和染色体易位特征，这些变化本身并不是恶性的原因。过去十年的纵向研究集中于识别恶性转化特征的特定多发性骨髓瘤PC固有的基因组变化，仅取得了轻微的成功，尽管已发现反复发生的突变，但患者之间存在显著的异质性，关于疾病进展的许多问题仍未得到解答。这一建议的主要焦点是在疾病从MGUS/SMM向恶性MM进展的过程中，骨髓微环境(ME)的变化以及与异常BMPC密切相关的天然免疫细胞和获得性免疫细胞之间的关系。BMPC免疫环境(原位免疫细胞的性质、密度、功能定位和空间关系)及其在MGUS/SMM向MM进展中的潜在作用尚未被研究过。我们的特定假设是，BM ME积极抑制MGUS和SMM患者的疾病进展，ME中的局部变化缓解了这种抑制，并允许这些修改的利基中的异常PC扩张。这些变化可能是由于年龄导致PC内细胞的组成或功能的偏离，或者可能是癌前细胞迁移到有利于疾病进展的利基中。我们还假设，BM ME的变化实际上可能是由异常PC本身及其释放的微囊(MV)驱动的，这些微囊在区域上扩大了BMPC的生态位并促进了全身扩散。因此，这项建议将集中在多发性骨髓瘤进展过程中PC和MV驱动的骨髓ME中免疫细胞的变化，这些变化的功能后果，以及与临床结果的相关性。

 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.