Microhomologies and Topoisomerase II Consensus Sequences Identified Near the Breakpoint Junctions of the Recurrent t(7;21)(p22;q22) Translocation in Acute Myeloid Leukemia
Microhomologies and Topoisomerase II Consensus Sequences Identified Near the Breakpoint Junctions of the Recurrent t(7;21)(p22;q22) Translocation in Acute Myeloid Leukemia
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DOI：
10.1002/gcc.20848
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发表时间：
2011-04-01
影响因子：
3.7
通讯作者：
Hebert, Josee
中科院分区：
文献类型：
--
作者：
Giguere, Amelie;Hebert, Josee
RUNX1重排是急性白血病中常见的基因异常。最近在三例髓系肿瘤中发现的t(7;21)（p22;q22）易位，将泛素特异性肽酶42基因USP42（去泛素化酶家族的一员）融合到RUNX1上。在这项研究中，我们描述了半隐型t(7; 21)（p22; q22）易位，通过荧光原位杂交和光谱核型鉴定，在一个新的急性髓系白血病病例。逆转录聚合酶链反应产物的序列分析证实存在两个框架内的RUNX1-USP42和一个框架内的USP42-RUNX1融合转录物。基因组易位断点的生物信息学分析揭示了微同源性和共享核苷酸在连接处的插入。在断裂位点附近也检测到拓扑异构酶II序列。此外，我们通过实时荧光定量PCR证实了t（7; 21）阳性细胞中重排USP42基因的显著过表达。我们的研究结果首次证明了非同源末端连接机制可能参与了复发性t（7; 21）易位的起源。此外，在推测的嵌合蛋白中存在完整的催化USP位点和USP42的上调表达表明去泛素化酶在这种白血病的发病机制中起作用。(C) 2011 Wiley-Liss, Inc。
RUNX1 rearrangements are common genetic abnormalities in acute leukemia. The t(7;21)(p22;q22) translocation, recently described in three cases of myeloid neoplasias, fuses the ubiquitin specific peptidase 42 gene, USP42, a member of the deubiquitinating enzyme family, to RUNX1. In this study, we characterized the semicryptic t(7; 21)(p22; q22) translocation, identified by fluorescent in situ hybridization and spectral karyotyping, in a novel case of acute myeloid leukemia. Sequence analysis of the reverse transcription-polymerase chain reaction products confirmed the presence of two in-frame RUNX1-USP42 and one reciprocal in-frame USP42-RUNX1 fusion transcripts. Bioinformatic analysis of the genomic translocation breakpoints revealed microhomologies and insertion of shared nucleotides at the junctions. A topoisomerase II sequence was also detected near the break site. Additionally, we demonstrated a significant overexpression of the rearranged USP42 gene in t(7; 21) positive cells using quantitative real-time PCR. Our results provide the first evidence of the possible involvement of the nonhomologous end-joining mechanism in the origin of the recurrent t(7; 21) translocation. Moreover, presence of the complete catalytic USP site in the putative chimeric proteins and the upregulated expression of USP42 suggest a role of the deubiquitinating enzyme in the pathogenesis of this leukemia. (C) 2011 Wiley-Liss, Inc.