多发性骨髓瘤肿瘤起始细胞的鉴定和特征。
Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma.
机构信息
Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA.
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
出版信息
J Natl Cancer Inst. 2020 May 1;112(5):507-515. doi: 10.1093/jnci/djz159.
BACKGROUND
Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant.
METHODS
Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group.
RESULTS
CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo.
CONCLUSION
Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.
背景
癌症（包括多发性骨髓瘤 [MM]）的治疗失败最有可能是由于肿瘤起始细胞（TIC）的一小部分持续存在所致，这些细胞处于非循环或缓慢循环状态，并且对药物具有很强的抵抗力。
方法
采用基因表达谱分析和实时定量逆转录聚合酶链反应，对来自 11 例 MM 患者样本的侧群细胞（其中包含 TIC）和 MM 细胞主群之间差异表达的基因进行鉴定。通过克隆形成和 CD24+MM 细胞的耐药性分析自更新潜能。流式细胞术（n=60）和免疫荧光（n=66）用于 MM 患者样本以确定 CD24 表达。CD24 抗体的治疗效果在每组包含三到六只小鼠的异种移植 MM 小鼠模型中进行了测试。
结果
CD24 在侧群细胞中高表达，CD24+MM 细胞表现出诱导多能或胚胎干细胞基因的高表达。CD24+MM 细胞表现出增加的集落形成能力、耐药性和致瘤性。仅需 10 个 CD24+MM 细胞即可在小鼠中发展为浆细胞瘤（n=五只小鼠中的三只，在 27 天后）。在原发性 MM 样本中，CD24+MM 细胞的频率变化很大，但与新诊断的 MM 样本中的 1.0% CD24+MM 细胞相比，化疗后和完全缓解的 MM 样本中 CD24+MM 细胞的平均值为 8.3%（n=26）。CD24+MM 细胞初始百分比高的 MM 患者无进展生存期（危险比 [HR] = 3.81，95%置信区间 [CI] = 5.66 至 18.34，P<.001）和总生存期（HR = 3.87，95%CI = 16.61 至 34.39，P=.002）较差。CD24 抗体抑制 MM 细胞生长并防止体内肿瘤进展。
结论
我们的研究表明，CD24+MM 细胞保持自我更新和耐药性的 TIC 特征，并为骨髓瘤治疗提供了一个靶标。
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