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

Benshang Li, Samuel W. Brady, Xiaotu Ma, Shuhong Shen, Yingchi Zhang, Yongjin Li, Karol Szlachta, Li Dong, Yu Liu, Fan Yang, Ningling Wang, Diane A. Flasch, Matthew A. Myers, Heather L. Mulder, Lixia Ding, Yanling Liu, Liqing Tian, Kohei Hagiwara, Ke Xu, Xin ZhouEdgar Sioson, Tianyi Wang, Liu Yang, Jie Zhao, Hui Zhang, Ying Shao, Hongye Sun, Lele Sun, Jiaoyang Cai, Hui Ying Sun, Ting Nien Lin, Lijuan Du, Hui Li, Michael Rusch, Michael N. Edmonson, John Easton, Xiaofan Zhu, Jingliao Zhang, Cheng Cheng, Benjamin J. Raphael, Jingyan Tang, James R. Downing, Ludmil B. Alexandrov, Bin Bing S. Zhou, Ching Hon Pui, Jun J. Yang, Jinghui Zhang

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)41-55
Number of pages15
JournalBlood
Volume135
Issue number1
DOIs
StatePublished - 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Li, B., Brady, S. W., Ma, X., Shen, S., Zhang, Y., Li, Y., Szlachta, K., Dong, L., Liu, Y., Yang, F., Wang, N., Flasch, D. A., Myers, M. A., Mulder, H. L., Ding, L., Liu, Y., Tian, L., Hagiwara, K., Xu, K., ... Zhang, J. (2020). Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia. Blood, 135(1), 41-55. https://doi.org/10.1182/blood.2019002220