Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia
Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia
复制标题
DOI：
10.1182/blood-2013-01-479188
复制
发表时间：
2013-07-04
期刊：
影响因子：
20.3
通讯作者：
Doehner, Konstanze
中科院分区：
文献类型：
--
作者：
Kroenke, Jan;Bullinger, Lars;Doehner, Konstanze
核磷蛋白1 （NPM1）基因的突变被认为是急性髓性白血病（AML）发病机制的一个创始事件。为了研究克隆进化在复发性NPM1突变（NPM1(mut)） AML中的作用，我们应用高分辨率、全基因组、单核苷酸多态性阵列分析来检测拷贝数改变（CNAs）和单染色体二体（UPDs），并对诊断和复发时获得的53对骨髓/外周血样本进行了全面的基因突变筛查。在诊断时，13例（25%）患者中发现15个畸变（CNAs, n = 10; upd, n = 5），而在复发时，29例（55%）患者中检测到56个基因组畸变（CNAs, n = 46; upd, n = 10），表明基因组复杂性增加。复发时获得的复发性畸变包括影响肿瘤抑制基因（ETV6 [n = 3], TP53 [n = 2], NF1 [n = 2], WT1 [n = 3], FHIT [n = 2]）的缺失和通过UPD13q获得的纯合子FLT3突变（n = 7）。DNMT3A突变（DNMT3A(mut)）的稳定性最高（97%）。5例复发时丢失NPM1（mut）的患者中DNMT3A（mut）的持续存在提示DNMT3A（mut）可能在AML发病机制中先于NPM1（mut）。值得注意的是，所有复发样本与匹配的原发性AML样本至少有一个遗传畸变，这意味着共同的祖先克隆。总之，我们的研究揭示了NPM1(mut) AML克隆进化的新见解。
Mutations in the nucleophosmin 1 (NPM1) gene are considered a founder event in the pathogenesis of acute myeloid leukemia (AML). To address the role of clonal evolution in relapsed NPM1-mutated (NPM1(mut)) AML, we applied high-resolution, genome-wide, single-nucleotide polymorphism array profiling to detect copy number alterations (CNAs) and uniparental disomies (UPDs) and performed comprehensive gene mutation screening in 53 paired bone marrow/peripheral blood samples obtained at diagnosis and relapse. At diagnosis, 15 aberrations (CNAs, n = 10; UPDs, n = 5) were identified in 13 patients (25%), whereas at relapse, 56 genomic alterations (CNAs, n = 46; UPDs, n = 10) were detected in 29 patients (55%) indicating an increase in genomic complexity. Recurrent aberrations acquired at relapse included deletions affecting tumor suppressor genes (ETV6 [n = 3], TP53 [n = 2], NF1 [n = 2], WT1 [n = 3], FHIT [n = 2]) and homozygous FLT3 mutations acquired via UPD13q (n = 7). DNMT3A mutations (DNMT3A(mut)) showed the highest stability (97%). Persistence of DNMT3A(mut) in 5 patients who lost NPM1(mut) at relapse suggests that DNMT3A(mut) may precede NPM1(mut) in AML pathogenesis. Of note, all relapse samples shared at least 1 genetic aberration with the matched primary AML sample, implying common ancestral clones. In conclusion, our study reveals novel insights into clonal evolution in NPM1(mut) AML.