Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice
Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice
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DOI：
10.1182/blood-2008-01-132084
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发表时间：
2008-08-15
期刊：
影响因子：
20.3
通讯作者：
Graubert, Timothy A.
中科院分区：
文献类型：
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作者：
Funk, Ryan K.;Maxwell, Taylor J.;Graubert, Timothy A.
治疗相关的急性髓性白血病（t-AML）是烷化剂化疗的一个重要的晚期不良反应。 t-AML 的易感性具有遗传因素，但影响易感性的特定遗传变异却知之甚少。我们分析了对烷基化剂乙基-N-亚硝基脲 (ENU) 诱导的 t-AML 耐药或敏感的小鼠品系之间的 F-2 杂交（n = 282 只小鼠），以鉴定调节 t-AML 易感性的基因。每只小鼠均携带 hCG-PML/RARA 转基因，这是一种已明确描述的髓系白血病引发剂。在没有 ENU 治疗的情况下，转基因 F-2 小鼠患白血病的发病率比耐药背景中的小鼠更高（79.4% vs 12.5%），而且发生时间点更早（108 天 vs 234 天）。 F2 小鼠的 ENU 治疗进一步增加了发病率（90.4%）并缩短了中位生存期（1171 天 vs 254 天）。我们对 F-2 小鼠基因组中 384 个信息性单核苷酸多态性进行了基因分型，并进行了数量性状基因座 (QTL) 分析。在 8 条染色体上鉴定出 13 个与无白血病生存、脾脏重量或白细胞计数显着相关的 QTL。这些结果表明，小鼠对 ENU 诱导的白血病的易感性是一个受多个位点基因控制的复杂性状。提高对遗传风险因素的了解应有助于制定量身定制的治疗方案，以降低易患 t-AML 的患者的风险。
Therapy-related acute myelogenous leukemia (t-AML) is an important late adverse effect of alkylator chemotherapy. Susceptibility to t-AML has a genetic component, yet specific genetic variants that influence susceptibility are poorly understood. We analyzed an F-2 intercross (n = 282 mice) between mouse strains resistant or susceptible to t-AML induced by the alkylator ethyl-N-nitrosourea (ENU) to identify genes that regulate t-AML susceptibility. Each mouse carried the hCG-PML/RARA transgene, a well-characterized initiator of myeloid leukemia. In the absence of ENU treatment, transgenic F-2 mice developed leukemia with higher incidence (79.4% vs 12.5%) and at earlier time points (108 days vs 234 days) than mice in the resistant background. ENU treatment of F2 mice further increased incidence (90.4%) and shortened median survival (1171 vs 254 days). We genotyped F-2 mice at 384 informative single nucleotide polymorphisms across the genome and performed quantitative trait locus (QTL) analysis. Thirteen QTLs significantly associated with leukemia-free survival, spleen weight, or white blood cell count were identified on 8 chromosomes. These results suggest that susceptibility to ENU-induced leukemia in mice is a complex trait governed by genes at multiple loci. Improved understanding of genetic risk factors should lead to tailored treatment regimens that reduce risk for patients predisposed to t-AML.