Prevention of MGUS Progression to MM by Modulating the Bone Marrow Microenvironment

项目摘要 这项工作的长期目标是确定骨髓微环境的功能作用 在调节意义不明的单克隆丙种球蛋白病（MGUS）的浆细胞生长中，使用 多个MGUS小鼠模型来定义可靠的生物标志物。我们的发现应该成为设计 新的治疗方法，以防止MGUS进展为多发性骨髓瘤（MM）。MGUS是一种癌前病变， 但在浆细胞（PC）中存在异常DNA变化的克隆状态。MGUS的患病率随着 年龄50岁时为3.2%，但85岁以上的人则上升至9%，这表明与 衰老在MGUS的发展中起重要作用。MGUS可能进展为郁积型多发性骨髓瘤 (SMM)和/或MM，需要治疗。因此，识别并随后锁定目标尤为重要 与MGUS进展相关的风险因素。通过研究MGUS小鼠模型和原代人 从MGUS患者的样本中，我们已经证明了骨髓细胞衰老与衰老有关， 铁代谢和MGUS浆细胞中增加的DKK 1与MGUS进展有关。我们假设 骨髓微环境（ME）的变化改变了MGUS浆细胞的基因表达， 诱导骨破坏和免疫抑制，导致MGUS浆细胞增殖和疾病 逃避有效的免疫监视。我们提出了三个具体的目标来证明这一假设：（1） 确定ME的细胞衰老在MGUS进展中的作用;（2）确定DKK 1在MGUS进展中的作用。 在过继转基因小鼠中促进MGUS进展;和（3）确定细胞和分子机制 MGUS进展。我们的目标是发现新的治疗方法，以防止人类MGUS 进展

PROJECT SUMMARY The long-term objective of this work is to determine the functional role of the bone marrow microenvironment in regulating the plasma cell growth of monoclonal gammopathy of undetermined significance (MGUS), using multiple MGUS mouse models to define reliable biomarkers. Our findings should form the basis for designing novel treatment approaches to prevent MGUS progression to multiple myeloma (MM). MGUS is a precancerous, but clonal condition with aberrant DNA changes in plasma cells (PC). The prevalence of MGUS increases with age. It is 3.2% at 50 years but rises to 9% for those older than 85, suggesting that risk factors associated with aging play an important role in MGUS development. MGUS may progress to smoldering multiple myeloma (SMM) and/or to MM, requiring therapy. Therefore, it is particularly important to identify and subsequently target the risk factors associated with MGUS progression. By studying MGUS mouse models and primary human samples from MGUS patients, we have demonstrated that bone marrow cellular senescence related to aging, iron metabolism, and increased DKK1 in MGUS plasma cells are linked to MGUS progression. We hypothesize that changes in the bone marrow microenvironment (ME) alter gene expression of MGUS plasma cells and induce both bone destruction and immunosuppression resulting in MGUS plasma cell proliferation and disease escape from effective immune surveillance. We propose three specific aims to prove this hypothesis: (1) determine the role of cellular senescence of ME in MGUS progression; (2) determine the role of DKK1 in promoting MGUS progression in adoptive transgenic mice; and (3) determine cellular and molecular mechanisms of MGUS progression. Our goal is to discover novel therapeutic approaches to prevent human MGUS progression.