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Identification of Fusion Genes and Characterization of Transcriptome Correction GENETICS Correction for “Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia,” by Bing Chen, Lu Jiang, Meng-Ling Zhong, Jian-Feng Li, Ben-Shang Li, Li-Jun Peng, Yu-Ting Dai, Bo-Wen Cui, Tian-Qi Yan, Wei-Na Zhang, Xiang-Qin Weng, Yin-Yin Xie, Jing Lu, Rui-Bao Ren, Su-Ning Chen, Jian-Da Hu, De-Pei Wu, Zhu Chen, Jing-Yan Tang, Jin-Yan Huang, Jian-Qing Mi, and Sai-Juan Chen, which was first published December 26, 2017; 10.1073/pnas.1717125115 (Proc. Natl. Acad. Sci. U.S.A. 115, 373–378). The authors note that the data deposition information in- cluded in the original publication is no longer valid. The data are now hosted at The National Omics Data Encyclopedia (NODE) (https://www.biosino.org/node). The data can be viewed via acces- sion no. OEP000760 or the following URL: https://www.biosino.org/ node/project/detail/OEP000760. The data deposition footnote has been updated online. Published under the PNAS license. First published September 8, 2020. www.pnas.org/cgi/doi/10.1073/pnas.2017617117 23192 | PNAS | September 15, 2020 | vol. 117 | no. 37 www.pnas.org Downloaded by guest on September 26, 2021 Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia Bing Chena,1, Lu Jianga,1, Meng-Ling Zhonga,1, Jian-Feng Lia,1, Ben-Shang Lib,1, Li-Jun Penga, Yu-Ting Daia, Bo-Wen Cuia, Tian-Qi Yana, Wei-Na Zhanga, Xiang-Qin Wenga, Yin-Yin Xiea, Jing Lua, Rui-Bao Rena, Su-Ning Chenc, Jian-Da Hud, De-Pei Wuc, Zhu Chena,2, Jing-Yan Tangb,2, Jin-Yan Huanga,2, Jian-Qing Mia,2, and Sai-Juan Chena,2 aState Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; bDepartment of Hematology and Oncology, Shanghai Institute of Hematology, Shanghai Children’s Medical Center, Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; cJiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow 215006, China; and dFujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, China Contributed by Zhu Chen, December 1, 2017 (sent for review September 29, 2017; reviewed by Hervé Dombret and Arnold Ganser) T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of RAS-MAPK pathway genes and CDKN2A/2B deletions (2, 5, immature T cells. Recently, the next-generation sequencing approach 12–15). has allowed systematic identification of molecular features in pediat- In recent years, next-generation sequencing techniques, in- ric T-ALL. Here, by performing RNA-sequencing and other genome- cluding whole-genome sequencing, whole-exome sequencing wide analysis, we investigated the genomic landscape in 61 adult and (WES), and RNA sequencing (RNA-seq), have extended the list of 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts genetic abnormalities in T-ALL to epigenetic factors and trans- were identified, with SET-NUP214 being highly related to adult cases. lation/RNA stability pathways (16–21). Of note, a subgroup of + − Among 18 previously unknown fusions, ZBTB16-ABL1, TRA-SALL2, T-ALL with a characteristic immunophenotype (CD3 /CD1a / − weak and involvement of NKX2-1 were recurrent events. ZBTB16-ABL1 CD8 /CD5 ) has been designated as early T-cell precursor ALL GENETICS functioned as a leukemogenic driver and responded to the effect of (ETP-ALL), with special gene mutation patterns (16, 22). The in- tyrosine kinase inhibitors. Among 48 genes with mutation rates >3%, tegrated analysis of gene alterations in two recent series of pediatric 6 were newly found in T-ALL. An aberrantly overexpressed short T-ALL provided an enlarged view of the genomic landscape in this mRNA transcript of the SLC17A9 gene was revealed in most cases heterogenous disease (20, 23). However, complex interplay of gene with overexpressed TAL1, which predicted a poor prognosis in the fusions, sequence abnormalities, and transcriptional expression adult group. Up-regulation of HOXA, MEF2C,andLYL1 was often profiles, especially in adult cases, needs to be further addressed to present in adult cases, while TAL1 overexpression was detected refine the current model of T-ALL leukemogenesis and to reveal mainly in the pediatric group. Although most gene fusions were mu- potential new biomarkers and therapeutic targets. tually exclusive, they coexisted with gene mutations. These genetic In this study, RNA-seq, WES, and other genomic analyses abnormalities were correlated with deregulated gene expression wereperformedin61adultand69pediatricT-ALLcases.Anumber markers in three subgroups. This study may further enrich the current of previously undescribed gene fusions, mutations, aberrant tran- knowledge of T-ALL molecular pathogenesis. scripts, and gene expression patterns were identified. Specifically, Significance T-ALL | transcriptome | fusion gene | ZBTB16-ABL1 | gene mutation To get more insights into the disease mechanism of T-cell acute T-cell acute lymphoblastic leukemia (T-ALL) is a clonal ma- lymphoblastic leukemia (T-ALL), particularly in an adult group, lignancy of immature T cells, accounting for 15% of pediatric we addressed the genomic landscape in 130 patients, including ALL and 25% of adult ALL. Currently, the 5-y survival rate of 61 cases of adult T-ALL. A number of new genetic aberrations pediatric T-ALL has reached more than 80% (1). In adult T- were identified using integrated transcriptome and genomic ALL, while significant therapeutic progress has been made in analysis. Distinct T-ALL subgroups were defined according to the advanced hematology/oncology centers with a 5-y survival rate of interplay among different genetic abnormalities and gene tran- over 60% (2), there are still challenges to improve the clinical scription patterns. Characterization of genomic features of T-ALL prognosis in many cases. A better understanding of T-ALL in an is valuable not only for a better understanding of leukemogen- adult group may allow more rational disease stratification and esis, but also for patient stratification and tailored therapy. precision therapy. Over the past three decades, many genetic – abnormalities have been found in T-ALL (3 5). Aberrant ex- Author contributions: Z.C. and S.-J.C. designed research; B.C., L.J., M.-L.Z., B.-S.L., L.-J.P., pression of genes such as LMO1, LMO2, TAL1, TLX1, TLX3, W.-N.Z., X.-Q.W., Y.-Y.X., J.L., R.-B.R., S.-N.C., J.-D.H., D.-P.W., J.-Y.T., and J.-Q.M. per- and other transcription factors (TFs) can be either due to formed research; B.C., J.-F.L., Y.-T.D., B.-W.C., T.-Q.Y., and J.-Y.H. analyzed data; and chromosomal rearrangements juxtaposing T-cell receptor (TCR) B.C., L.J., Z.C., J.-Y.H., J.-Q.M., and S.-J.C. wrote the paper. loci to these genes or due to the recently described somatic Reviewers: H.D., Unité INSERM 462, Hôpital Saint-Louis; and A.G., Hannover Medical School. mutations in enhancer regions recruiting relevant TFs such as The authors declare no conflict of interest. MYB (6, 7). These abnormalities can be detected in 40–50% T-ALL (8). On the other hand, fusion genes are also common (20–30% in Published under the PNAS license. T-ALL), generating overexpression of mRNAs with ORFs for Data deposition: The datasets reported in this paper have been deposited in the Chinese TAL1 STIL-TAL1 Leukemia Genotype-Phenotype Archive, bioinfo.rjh.com.cn/cga (accession no. wild-type protein (such as in ) (9, 10) or tran- CGAS00000000002). scripts containing fusions between two truncated ORFs such as 1 SET-NUP214 B.C., L.J., M.-L.Z., J.-F.L., and B.-S.L. contributed equally to this work. (11). A number of gene abnormalities in path- 2To whom correspondence may be addressed. Email: [email protected], tangjingyan@scmc. ways regulating differentiation, proliferation, self-renewal, and com.cn, [email protected], [email protected], or [email protected]. survival of T-cell precursors are also found in high frequencies, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. such as mutations of NOTCH1, JAK-STAT, PI3K-AKT, or 1073/pnas.1717125115/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1717125115 PNAS Early Edition | 1of6 Table 1. Clinical characteristics of 130 patients with T-ALL recurrent events (Dataset S3). Four types of gene abnormalities ZBTB16- Adult Child were identified among previously unknown fusions. In ABL1, the N-terminal moiety of ZBTB16 was fused to the body Characteristics (n = 61), n (%) (n = 69), n (%) P value region of ABL1, defining a typical chimeric ORF (type 1). The Gender, male/female 42/19 53/16 0.307 type 2 fusion was represented by case C47 where the 5′ un- Age, y, median (range) 34 (18–62) 11 (1–17) translated region (UTR) of EVL, a gene highly expressed in T- WBC count 0.004 ALL cells found in this work (SI Appendix,Fig.S3A), was fused to NKX2-1 ≥100 × 109/L 15 (24.6) 34 (49.3) the entire ORF of homeobox gene . This fusion led to an < × 9 aberrantly high expression of NKX2-1 (SI Appendix,Fig.S3B). In 100 10 /L 46 (75.4) 35 (50.7) EVL SFTA3 Immunophenotype the same case, an - fusion was also detected, probably caused by a splicing between EVL and SFTA3, the latter being ETP 17 (27.9) 7 (10.1) 0.009 NKX2-1 Pro 6 (9.8) 3 (4.3) 0.219 located downstream from (Fig. 1). Type 3 fusion was characterized by genes fused to TCR-alpha, -beta, or -delta (TRA/ Pre 13 (21.3) 21 (30.4) 0.238 TRB/TRD) loci, leading to overexpression of SALL2 [a TF de- Cortical 18 (29.5) 28 (40.6) 0.188 regulated in various cancers (27)] and NKX2-1 (SI Appendix, Fig.
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