Department of Medicine, Columbia University Medical Center, Columbia University, Milstein Hospital Building, 6N-435, 177 Fort Washington Avenue, New York, NY, 10032, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, Columbia University, New York, NY, USA.
Curr Treat Options Oncol. 2018 Oct 25;19(12):66. doi: 10.1007/s11864-018-0583-4.
Aging is the most potent of carcinogens, especially for the bone marrow stem cell clonal disorders called myelodysplastic syndromes (MDS). Age-associated changes in the microenvironment or the soil of the bone marrow (BM) as well as in the cell or the seed provide a growth advantage for clonal myeloid cells. Slowly accumulating senescent cells which can no longer divide because they have reached the end of their proliferative life cycle, but which continue to produce metabolic debris, overwhelm the natural autophagy mechanisms resulting in pro-inflammatory changes in the BM soil. In addition, the seed or stem cells acquire passenger mutations with each round of proliferation resulting from DNA copying errors. Some mutations commonly associated with MDS can be found in older, otherwise healthy individuals; however, when combined with other passenger mutations or in the setting of a noxious soil, the result could be a proliferative advantage for one stem cell over others, leading to its clonal expansion and development of the clinical syndrome. When considering therapeutic options for MDS patients, the important considerations are related to both the common co-morbidities of an elderly population along with the heterogeneous passenger mutations and the inflammatory changes in the soil. At present, allogeneic stem cell transplant is the only potentially curative option in MDS. Palliative strategies are directed at improving the quality of life and prolonging survival. Only three drugs are FDA approved, two being the hypomethylating agents azacytidine and decitabine while the third is lenalidomide which is restricted to lower risk MDS patients with deletion 5q. Promising future therapies are directed at reversing the pro-inflammatory changes in the microenvironment (luspatercept) or targeting specific mutations isocitrate dehydrogenase (IDH)1, IDH2, p53, EZH2. More durable responses are to be expected when the seed and soil are targeted simultaneously through a combination of drugs.
衰老是最强的致癌因素，尤其对骨髓干细胞克隆紊乱，即骨髓增生异常综合征（MDS）。骨髓微环境或土壤、细胞或种子的衰老相关变化为克隆性髓系细胞提供了生长优势。缓慢积累的衰老细胞由于已达到增殖生命周期的终点而无法再分裂，但它们继续产生代谢废物，超过了自然自噬机制，导致骨髓土壤发生促炎变化。此外，种子或干细胞在每一轮因 DNA 复制错误而增殖时获得乘客突变。一些常见于 MDS 的突变可以在年龄较大但其他方面健康的个体中发现；然而，当与其他乘客突变或在有害土壤环境中结合时，结果可能是一个干细胞相对于其他干细胞具有增殖优势，导致其克隆性扩张并发展为临床综合征。在考虑 MDS 患者的治疗选择时，重要的考虑因素与老年人群的常见合并症以及土壤中的异质性乘客突变和炎症变化有关。目前，异基因干细胞移植是 MDS 唯一潜在的治愈选择。姑息性策略旨在提高生活质量并延长生存时间。仅有三种药物获得 FDA 批准，其中两种是低甲基化剂阿扎胞苷和地西他滨，第三种是来那度胺，仅限于具有 5q 缺失的低风险 MDS 患者。有前途的未来疗法旨在逆转微环境中的促炎变化（luspatercept）或针对特定突变异柠檬酸脱氢酶（IDH）1、IDH2、p53、EZH2。当通过联合用药同时靶向种子和土壤时，预计会有更持久的反应。
