Authors' Affiliations: Charles Bruneau Cancer Center, Research Center CHU Sainte-Justine; Departments of Pediatrics and Pharmacology, University of Montreal; Department of Diagnostic Medicine, Jewish General Hospital, Montreal, Quebec, Canada; Departments of Pediatric Oncology and Biostatistics and Computational Biology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Children's Hospital; and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
Clin Cancer Res. 2013 Sep 15;19(18):5240-9. doi: 10.1158/1078-0432.CCR-13-1215. Epub 2013 Aug 1.
Corticosteroids induce apoptosis in the malignant lymphoid cells and are critical component of combination therapy for acute lymphoblastic leukemia (ALL). Several genome-wide microarray studies showed major implication of proapoptotic Bim in mediating corticosteroid-related resistance in leukemia cells.
We investigated Bim gene polymorphisms and their association with childhood ALL outcome, and the mechanism underlying the observed finding.
Lower overall survival (OS) was associated with Bim C29201T located in Bcl-2 homology 3 (BH3) domain (P = 0.01). An association remained significant in multivariate model (P = 0.007), was more apparent in high-risk patients (P = 0.004) and patients treated with dexamethasone (P = 0.009), and was subsequently confirmed in the replication patient cohort (P = 0.03). RNA analysis revealed that C29201T affects generation of γ isoforms (γ1) that lack proapoptotic BH3 domain. The phenotypic effect was minor suggesting the influence of additional factors that may act in conjunction with Bim genotype. Combined analysis with Mcl gene polymorphism (G-486T) revealed profound reduction in OS in individuals with both risk genotypes (P < 0.0005 in discovery and P = 0.002 in replication cohort) and particularly in high-risk patients (P ≤ 0.008).
Increased expression of prosurvival Mcl1 and presence of Bim isoforms lacking proapoptotic function might explain marked reduction of OS in a disease and dose-dependent manner in ALL patients carrying Bim- and Mcl1-risk genotypes.
皮质类固醇可诱导恶性淋巴样细胞凋亡，是急性淋巴细胞白血病（ALL）联合治疗的重要组成部分。几项全基因组微阵列研究表明，促凋亡 Bim 在介导白血病细胞中皮质类固醇相关耐药性方面具有重要意义。
我们研究了 Bim 基因多态性及其与儿童 ALL 结局的关系，并探讨了观察结果的潜在机制。
总体生存（OS）较低与位于 Bcl-2 同源结构域 3（BH3）的 Bim C29201T 有关（P = 0.01）。在多变量模型中，这种相关性仍然具有统计学意义（P = 0.007），在高危患者（P = 0.004）和接受地塞米松治疗的患者（P = 0.009）中更为明显，并且随后在复制患者队列中得到证实（P = 0.03）。RNA 分析表明，C29201T 影响缺乏促凋亡 BH3 结构域的 γ 同种型（γ1）的产生。表型效应较小，表明可能存在与 Bim 基因型共同作用的其他因素。与 Mcl 基因多态性（G-486T）的联合分析表明，在具有两种风险基因型的个体中，OS 显著降低（在发现队列中 P < 0.0005，在复制队列中 P = 0.002），尤其是在高危患者中（P ≤ 0.008）。
在 ALL 患者中，具有 Bim 和 Mcl1 风险基因型的患者，Mcl1 表达增加，缺乏促凋亡功能的 Bim 同种型的存在，可能以疾病和剂量依赖的方式解释 OS 显著降低。
