文章：

拷贝中性的杂合性缺失在FLT3/ITD AML的发病机制中很普遍，是一个晚期事件

Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML

原文发布日期：2014-05-02

DOI: 10.1038/bcj.2014.27

类型: Original Article

开放获取: 是

英文摘要：

Patients with high FLT3 internal tandem duplication allelic ratios (FLT3/ITD-ARs) have a poor prognosis. Single-nucleotide polymorphism/comparative genomic hybridization, single-cell PCR and colony-forming assays were used to evaluate genotypic evolution of high FLT3/ITD-ARs in 85 acute myeloid leukemia (AML) patients. Microarrays were used to examine molecular pathways disrupted in leukemic blasts with high FLT3/ITD-ARs. Copy-neutral loss of heterozygosity (CN-LOH) was identified at the FLT3 locus in diagnostic samples with high FLT3/ITD-ARs (N=11), but not in samples with low FLT3/ITD-ARs (N=24), FLT3-activating loop mutations (N=11) or wild-type FLT3 (N=39). Single-cell assays showed that homozygous FLT3/ITD genotype was present in subsets of leukemic blasts at diagnosis but became the dominant clone at relapse. Less differentiated CD34+/CD33− progenitor colonies were heterozygous for FLT3/ITD, whereas more differentiated CD34+/CD33+ progenitor colonies were homozygous for FLT3/ITD. Expression profiling revealed that samples harboring high FLT3/ITD-ARs aberrantly expressed genes within the recombination/DNA repair pathway. Thus, the development of CN-LOH at the FLT3 locus, which results in high FLT3/ITD-ARs, likely represents a late genomic event that occurs after the acquisition of the FLT3/ITD. Although the etiology underlying the development of CN-LOH remains to be clarified, the disruption in recombination/DNA repair pathway, which is present before the development of LOH, may have a role.

摘要翻译： 

FLT3内部串联重复等位基因比率（FLT3/ITD-AR）高的患者预后较差。本研究采用单核苷酸多态性/比较基因组杂交、单细胞PCR和集落形成实验，对85例急性髓系白血病（AML）患者高FLT3/ITD-AR的基因型演变进行了评估。通过微阵列技术检测了高FLT3/ITD-AR白血病母细胞中紊乱的分子通路。在高FLT3/ITD-AR的诊断样本（N=11）中，FLT3基因座存在拷贝数中性杂合性缺失（CN-LOH），而在低FLT3/ITD-AR（N=24）、FLT3激活环突变（N=11）或野生型FLT3（N=39）样本中均未发现。单细胞分析显示，诊断时白血病母细胞亚群中存在纯合型FLT3/ITD基因型，但在复发时成为优势克隆。分化程度较低的CD34+/CD33−祖细胞集落为FLT3/ITD杂合型，而分化程度较高的CD34+/CD33+祖细胞集落则为FLT3/ITD纯合型。表达谱分析显示，携带高FLT3/ITD-AR的样本异常表达重组/DNA修复通路相关基因。因此，FLT3基因座CN-LOH的形成（导致高FLT3/ITD-AR）可能是在获得FLT3/ITD后发生的晚期基因组事件。虽然CN-LOH形成的潜在病因尚待阐明，但在LOH形成前已存在的重组/DNA修复通路紊乱可能发挥了重要作用。

原文链接：

Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML