Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia
Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia
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T 细胞急性淋巴细胞白血病融合基因的鉴定和转录组特征的表征。
DOI：
10.1073/pnas.1717125115
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发表时间：
2018-01-09
影响因子：
11.1
通讯作者：
Hu, Jian-Da
中科院分区：
文献类型：
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作者：
Chen, Bing;Jiang, Lu;Hu, Jian-Da
T细胞急性淋巴细胞白血病（T-ALL）是一种未成熟T细胞的克隆性恶性肿瘤。最近，下一代测序方法已经允许系统地鉴定儿科T-ALL的分子特征。在这里，通过进行RNA测序和其他全基因组分析，我们研究了61例成人和69例儿童T-ALL病例的基因组景观。鉴定出36种不同的基因融合转录物，其中SET-NUP 214与成人病例高度相关。在18例先前未知的融合中，ZBTB 16-ABL 1、TRA-SALL 2和NKX 2 -1受累是复发事件。ZBTB 16-ABL 1作为致白血病驱动因子发挥作用，并对酪氨酸激酶抑制剂的作用作出反应。在突变率> 3%的48个基因中，有6个是在T-ALL中新发现的。SLC 17 A9基因的短mRNA转录本异常过表达在大多数过表达的TAL 1病例中被揭示，这预示着成人组的预后不良。HOXA、MEF 2C和LYL 1的上调通常存在于成人病例中，而TAL 1的过表达主要在儿科组中检测到。虽然大多数基因融合是相互排斥的，但它们与基因突变共存。这些遗传异常与三个亚组中的基因表达标志物失调相关。本研究可能进一步丰富目前对T-ALL分子发病机制的认识。
T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA-sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with SET-NUP214 being highly related to adult cases. Among 18 previously unknown fusions, ZBTB16-ABL1, TRA-SALL2, and involvement of NKX2-1 were recurrent events. ZBTB16-ABL1 functioned as a leukemogenic driver and responded to the effect of tyrosine kinase inhibitors. Among 48 genes with mutation rates >3%, 6 were newly found in T-ALL. An aberrantly overexpressed short mRNA transcript of the SLC17A9 gene was revealed in most cases with overexpressed TAL1, which predicted a poor prognosis in the adult group. Up-regulation of HOXA, MEF2C, and LYL1 was often present in adult cases, while TAL1 overexpression was detected mainly in the pediatric group. Although most gene fusions were mutually exclusive, they coexisted with gene mutations. These genetic abnormalities were correlated with deregulated gene expression markers in three subgroups. This study may further enrich the current knowledge of T-ALL molecular pathogenesis.