Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia.

Autor:	Li B; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and.; Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Brady SW; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Ma X; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Shen S; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and.; Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhang Y; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital-Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China., Li Y; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Szlachta K; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Dong L; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Liu Y; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Yang F; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and.; Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang N; Department of Pediatrics, the Second Hospital of Anhui Medical University, Hefei, China., Flasch DA; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Myers MA; Department of Computer Science, Princeton University, Princeton, NJ., Mulder HL; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Ding L; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and.; Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Liu Y; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Tian L; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Hagiwara K; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Xu K; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Zhou X; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Sioson E; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Wang T; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and., Yang L; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and., Zhao J; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and., Zhang H; Department of Pediatric Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China., Shao Y; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Sun H; WuXi NextCODE Co., Ltd, Shanghai, China., Sun L; WuXi NextCODE Co., Ltd, Shanghai, China., Cai J; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and., Sun HY; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and., Lin TN; Department of Pharmaceutical Sciences., Du L; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and.; Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Li H; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and.; Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Rusch M; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Edmonson MN; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Easton J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN., Zhu X; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital-Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China., Zhang J; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital-Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China., Cheng C; Department of Biostatistics, and., Raphael BJ; Department of Computer Science, Princeton University, Princeton, NJ., Tang J; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and., Downing JR; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, TN., Alexandrov LB; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA; and., Zhou BS; Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and.; Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Pui CH; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Yang JJ; Department of Pharmaceutical Sciences., Zhang J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Jan 02; Vol. 135 (1), pp. 41-55.
DOI:	10.1182/blood.2019002220
Abstrakt:	To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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