Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia.
Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia.
复制标题
DOI：
10.1001/jama.2010.1862
复制
发表时间：
2010-12-22
影响因子：
120.7
通讯作者：
Alizadeh, Ash A.
中科院分区：
文献类型：
--
作者：
Gentles, Andrew J.;Plevritis, Sylvia K.;Majeti, Ravindra;Alizadeh, Ash A.
在许多癌症中，特定的细胞亚群似乎具有独特的启动和维持肿瘤的能力。对这种癌症干细胞模型最有力的支持来自免疫缺陷小鼠的移植试验，该试验表明人类急性髓性白血病（AML）是由自我更新的白血病干细胞（LSC）驱动的。该模型对新疗法的开发具有重要意义，但其临床意义尚未确定。鉴定白血病干细胞基因表达特征并测试其与 AML 临床结果的关联。对原发性 AML 和正常患者样本中富含 LSC 的亚群的整体基因表达（微阵列）谱进行了分析。患者样本于 2005 年 4 月至 2007 年 7 月期间在斯坦福大学医学中心获得。对来自四个独立队列（总计 1047 名患者）的 AML 肿瘤全局转录谱的验证数据集进行了回顾性分析。鉴别 AML 肿瘤中富含 LSC 的基因与其他亚群的区别； LSC 特异性基因与总体生存率、无事件生存率和无复发生存率以及治疗反应的关联。在细胞分选的 AML 样本中，52 个基因的表达水平将富含 LSC 的细胞与其他亚群区分开来。定义了总结这些基因在大量原发性 AML 肿瘤样本中表达的 LSC 评分，并发现该评分与四个独立患者队列的临床结果相关。在核型正常 (NKAML) 或染色体异常的患者中，高 LSC 评分与较差的总生存 (OS)、无事件 (EFS) 和无复发 (RFS) 生存相关。对于最大的 NKAML 患者队列 (n=163)，LSC 评分作为连续变量与 OS 显着相关（风险比 [HR] 1.15，95% 置信区间 [CI] 1.08-1.22，对数似然 p<0.001）。当患者被分为高LSC评分组和低LSC评分组时，低LSC评分组的3年绝对死亡风险为57%（95% CI 43-67%），而高LSC评分组为78%（95% CI 66-86%）（HR 1.9，95% CI 1.3-2.7，对数秩p=0.002）。在另一个包含 70 名 NKAML 患者 EFS 可用数据的队列中，低 LSC 评分组 3 年内发生事件的风险为 48% (95% CI 27-63%)，而高 LSC 评分组为 81% (95% CI 60-91%)（HR 2.4，95% CI 1.3-4.5，对数秩 p=0.006）。 LSC 评分与较差的预后相关，独立于已知的预后因素，包括年龄、FLT3 或 NPM1 突变以及细胞遗传学风险组，并增加了其预后价值。对于包含细胞遗传学异常患者的三个队列中的 OS，多变量 Cox 回归中 FLT3/NPM1 状态、年龄和细胞遗传学风险组的连续 LSC 评分的 HR 分别为 HR 1.07 (95% CI 1.01-1.13)，p=0.02； HR 1.10（95% CI 1.03-1.17），p=0.005； HR 1.17（95% CI 1.05-1.30），p=0.005。白血病干细胞基因表达特征的高表达与 AML 的不良后果独立相关。
In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immune-deficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemia stem cells (LSC). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined. To identify a leukemic stem cell gene expression signature and test its association with clinical outcomes in AML. Global gene expression (microarray) profiles of LSC-enriched subpopulations from primary AML and normal patient samples were analyzed. Patient samples were obtained at Stanford University Medical Center between April 2005 and July 2007. Validation datasets of global transcriptional profiles of AML tumors from four independent cohorts totaling 1047 patients were analyzed retrospectively. Identification of genes discriminating LSC-enriched from other subpopulations in AML tumors; association of the LSC-specific genes with overall, event-free, and relapse-free survival, and with therapeutic response. Expression levels of 52 genes distinguished LSC-enriched from other subpopulations in cell-sorted AML samples. An LSC score summarizing expression of these genes in bulk primary AML tumor samples was defined and found to be associated with clinical outcomes in four independent patient cohorts. High LSC scores were associated with worse overall (OS), event-free (EFS), and relapse-free (RFS) survival, among patients with either a normal karyotype (NKAML), or with chromosomal abnormalities. For the largest cohort of patients with NKAML (n=163), the LSC score was significantly associated with OS as a continuous variable (hazard ratios [HR] 1.15, 95% Confidence Interval [CI] 1.08-1.22, log-likelihood p<0.001). When patients were split into high and low LSC score groups, the absolute risk of death by 3 years was 57% (95% CI 43-67%) for the low LSC score group, versus 78% (95% CI 66-86%) in the high LSC score group (HR 1.9, 95% CI 1.3-2.7, log-rank p=0.002). In another cohort with available data on EFS for 70 patients with NKAML, the risk of an event by 3 years was 48% (95% CI 27-63%) in the low LSC score group vs. 81% (95% CI 60-91%) in the high LSC score group (HR 2.4, 95% CI 1.3-4.5, log-rank p=0.006). The LSC score was associated with poorer outcomes, independently of known prognostic factors including age, FLT3 or NPM1 mutations, and cytogenetic risk group, and added to their prognostic value. For OS in three cohorts that included patients with cytogenetic abnormalities, the HRs of the continuous LSC score in multivariate Cox regression with FLT3/NPM1 status, age, and cytogenetic risk group were respectively HR 1.07 (95%CI 1.01-1.13), p=0.02; HR 1.10 (95% CI 1.03-1.17), p=0.005; and HR 1.17 (95% CI 1.05-1.30), p=0.005. High expression of a leukemic stem cell gene expression signature is independently associated with adverse outcomes in AML.
登录
查看更多内容
影响因子：
11.4
作者：
Costello, RT;Mallet, F;Olive, D
通讯作者：
Olive, D
影响因子：
20.3
作者：
Guzman, Monica L.;Li, Xiaojie;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
20.3
作者：
Guzman, ML;Rossi, RM;Jordan, CT
通讯作者：
Jordan, CT
影响因子：
17.1
作者：
Koscielny, Serge
通讯作者：
Koscielny, Serge