论文部分内容阅读
多发性骨髓瘤是一种常见的血液系统恶性肿瘤,其发病率在血液系统恶性肿瘤中居第二位,目前仍不可治愈。且多发性骨髓瘤患者生存时间跨度大,短至数月,长达15年以上,这说明骨髓瘤患者间存在遗传异质性,表现为分化程度不一及细胞和分子遗传特征的差异。阿肯色州立医学院骨髓瘤研究治疗中心是世界上接受和治疗骨髓瘤病人最多的医院,我们采集了初诊和大剂量化疗后的多发性骨髓瘤患者浆细胞,经纯化后用基因芯片技术得到了全基因组表达谱,并成功地用于多发性骨髓瘤分子水平的诊断、预后和指导治疗。根据基因表达谱的不同,我们确定了多发性骨髓瘤含有7个不同的遗传亚型。经监督聚类,找出可作为骨髓瘤高风险标志的70个基因,这些基因与病人的存活时间显著相关,且它们30%位于1号染色体上。CKS1B基因就是一个位于染色体1q21,与病人短期内死亡高度相关的重要候选瘤基因。通过深入的基因功能研究证明此基因通过SKP2和p27(kip1)依赖和非依赖机制影响多发性骨髓瘤细胞的增殖,本研究为建立针对性抑制CKS1B治疗方案治疗高风险多发性骨髓瘤患者奠定了理论基础。
Multiple myeloma is a common hematological malignancy, the incidence of which ranks second in hematological malignancies and remains incurable. And multiple myeloma patients with large span of life, as short as a few months, up to 15 years or more, indicating that there is genetic heterogeneity among patients with myeloma, manifested as varying degrees of differentiation and genetic characteristics of cells and molecular differences. Arkansas State Medical College Myeloma Research Treatment Center is the world’s largest hospital for patients receiving and treating myeloma. We collected plasma cells from patients with multiple myeloma after initial and high-dose chemotherapy and purified them using gene chip technology Genome profiling and successfully used in the diagnosis, prognosis and therapy of multiple myeloma at molecular level. Depending on the gene expression profile, we determined that multiple myeloma contains seven different genetic subtypes. After supervised clustering, 70 genes were identified as markers of high risk for myeloma, which are significantly associated with patient survival and 30% of them are located on chromosome 1. The CKS1B gene is an important candidate tumor gene located on chromosome 1q21, which is highly correlated with the short-term death of patients. In-depth gene function studies demonstrated that this gene affects the proliferation of multiple myeloma cells through SKP2 and p27 (kip1) -dependent and independent mechanisms. This study laid the foundation for the establishment of targeted inhibition of CKS1B treatment in patients with high-risk multiple myeloma Theoretical basis.