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Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs

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Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs Published OnlineFirst February 21, 2020; DOI: 10.1158/2159-8290.CD-19-1059 RESEARCH ARTICLE Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs Stephanie M. Dobson1,2, Laura García-Prat2, Robert J. Vanner1,2, Jeffrey Wintersinger3, Esmé Waanders4,5,6, Zhaohui Gu6, Jessica McLeod2, Olga I. Gan2, Ildiko Grandal7, Debbie Payne-Turner6, Michael N. Edmonson8, Xiaotu Ma8, Yiping Fan8, Veronique Voisin1,9, Michelle Chan-Seng-Yue2,10, Stephanie Z. Xie2, Mohsen Hosseini2, Sagi Abelson2, Pankaj Gupta8, Michael Rusch8, Ying Shao11, Scott R. Olsen12, Geoffrey Neale12, Steven M. Chan2, Gary Bader1,9, John Easton11, Cynthia J. Guidos13,14, Jayne S. Danska7,13,14, Jinghui Zhang8, Mark D. Minden2,15, Quaid Morris1,3,9,16, Charles G. Mullighan6, and John E. Dick1,2 ABSTRACT Disease recurrence causes significant mortality in B-progenitor acute lymphoblas- tic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples shows relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequenc- ing, identified and isolated minor diagnosis subclones that initiate an evolutionary trajectory toward relapse [termed diagnosis Relapse Initiating clones (dRI)]. Compared with other diagnosis subclones, dRIs were drug-tolerant with distinct engraftment and metabolic properties. Transcriptionally, dRIs displayed enrichment for chromatin remodeling, mitochondrial metabolism, proteostasis programs, and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy-resistant. SIGNIFICANCE: Isolation and characterization of subclones from diagnosis samples of patients with B-ALL who relapsed showed that relapse-fated subclones had increased drug tolerance and distinct metabolic and survival transcriptional programs compared with other diagnosis subclones. This study provides strat- egies to identify and target clinically relevant subclones before further evolution toward relapse. See related article by E. Waanders et al. 1Department of Molecular Genetics, University of Toronto, Toronto, of Medicine, University of Toronto, Toronto, Ontario, Canada. 16Vector Ontario, Canada. 2Princess Margaret Cancer Centre, University Health Institute, Toronto, Canada. Network, Toronto, Ontario, Canada. 3Department of Computer Science, Note: Supplementary data for this article are available at Cancer Discovery University of Toronto. Toronto, Ontario, Canada. 4Princess Máxima Center Online (http://cancerdiscovery.aacrjournals.org/). for Pediatric Oncology, Utrecht, the Netherlands. 5Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands. 6Depart- L. García-Prat, R.J. Vanner, J. Wintersinger, and E. Waanders contributed ment of Pathology, St. Jude Children’s Research Hospital, Memphis, equally to this article. Tennessee. 7Genetics and Genome Biology, Hospital for Sick Children Corresponding Authors: John E. Dick, Princess Margaret Cancer Centre, Research Institute, Toronto, Ontario, Canada. 8Department of Computa- University Health Network, University of Toronto, Princess Margaret Cancer tional Biology and Bioinformatics, St. Jude Children’s Research Hospi- Research Tower, 101 College Street, Toronto, Ontario M5G 1L7, Canada. Phone: tal, Memphis, Tennessee. 9Donnelly Centre for Cellular and Biomolecular 416-581-7472; Fax: 416-581-7476; E-mail: [email protected]; Research, Toronto, Ontario, Canada. 10PanCuRx Translational Research and Charles G. Mullighan, St. Jude Children’s Research Hospital, 262 Danny Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Thomas Place, Mailstop 342, Memphis, TN 38105, Phone: 901-595-3387; 11Pediatric Cancer Genome Project Laboratory, St. Jude Children’s Fax: 901-595-5947; E-mail: [email protected] Research Hospital, Memphis, Tennessee. 12Hartwell Center for Bioinfor- Cancer Discov 2020;10:568–87 matics and Biotechnology, St. Jude Children’s Research Hospital, Memphis, Tennessee. 13Developmental & Stem Cell Biology Program, Hospital for doi: 10.1158/2159-8290.CD-19-1059 Sick Children Research Institute, Toronto, Ontario, Canada. 14Department ©2020 American Association for Cancer Research. of Immunology, University of Toronto, Toronto, Ontario, Canada. 15Faculty 568 | CANCER DISCOVERY APRIL 2020 AACRJournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst February 21, 2020; DOI: 10.1158/2159-8290.CD-19-1059 from single-cell analysis, has largely substantiated these pre- INTRODUCTION dictions (8, 9). Functional studies to explain therapy failure Despite significant advancements in the treatment of acute have mainly been undertaken by comparing diagnosis cells lymphoblastic leukemia (ALL), the disease recurs in 15% to with those from relapse and identifying drug-resistance mecha- 20% of pediatric and 40% to 75% of adult patients, with the nisms present in relapse and absent at diagnosis. However, prognosis for patients who relapse being dismal (1–3). Analysis the properties of the relapse samples have been shaped by expo- of paired diagnosis and relapse ALL samples with increasingly sure to chemotherapy, causing further evolution and mutagen- broader and deeper genomic-sequencing methods has shown esis. Thus, two critical questions remain: What are the unique that classic Darwinian branching evolution of genomically properties and mechanisms that contribute to the relapse fate distinct subclones is a hallmark of disease recurrence (4, 5). of a particular diagnosis subclone prior to full evolution to At both diagnosis and relapse, a single neoplasm may con- drug-resistant relapse disease, and when does drug tolerance tain multiple genetic subclones related to each other through arise? Drug tolerance may arise stochastically through genetic complex evolutionary trajectories (4–7). Although relapse may or epigenetic mechanisms prior to exposure to therapy, and evolve from the predominant clone at diagnosis, in the major- be selected for by both cell-autonomous and non–cell autono- ity of patients relapse arises from preexisting minor subclones mous processes (10–13). Alternatively, therapy may induce within the diagnosis sample or from a rare ancestral clone (4–6). genomic aberrations that are then selected for during disease Although the population-level genetic analyses upon which progression, particularly if such alterations reduce leukemic these conclusions are based rely on computational inference cell fitness (14) during disease establishment and prior to the of their evolutionary relationships from analysis of bulk leu- administration of therapy (14, 15, 16). Without isolation of kemic cells, resolution of leukemic subclones at clonal lev- the subclones that contribute to disease progression from diag- els, either through isolation of subclones in xenografts or nosis samples, it is not possible to answer these questions and April 2020 CANCER DISCOVERY | 569 Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst February 21, 2020; DOI: 10.1158/2159-8290.CD-19-1059 RESEARCH ARTICLE Dobson et al. uncover the cellular and molecular properties that explain their B-ALL of varying genetic subtypes were undertaken to iden- differing subclonal fates and drug tolerance. tify somatic single-nucleotide variants (SNV), insertion– Many therapy resistance mechanisms have been implicated in deletion mutations (indels), and DNA copy-number altera- B-progenitor ALL (B-ALL), including acquisition of stemness tions (CNA). The patients encompassed a range of cytoge- programs, dormancy, the protective role of the niche, and the netic subtypes and varied in the length of their disease acquisition of resistance driver mutations (14, 17–21). How- remission (range 5.88–94.8 months; Supplementary Table ever, the ability to evade drug treatment is only one prerequisite S1). Diagnosis samples had a median of 24 somatic SNV/ of relapse; surviving cells must also possess significant clonal indels (range 7–100) and 13.5 CNA (range 1–51), whereas regenerative capacity to regrow or reproduce disease. For many relapse samples contained a median of 39.5 SNV/indels human cancers, only rare fractions of malignant cells are (range 22–405) and 16.5 CNA (range 2–58; Supplemen- capable of significant clonal propagation as detected by xen- tary Table S1). Leukemic variants were confirmed by tar- ograft-based cancer or leukemia-initiating cell (L-IC) assays geted sequencing using a custom capture array of the (10). Indeed, methods to propagate primary human leuke- variants identified by WES (Fig. 1A). Targeted sequencing mia samples were first undertaken in B-ALL with patient- and WES data were merged, resulting in a coverage of derived xenografts (PDX) recapitulating many features of approximately 350×. Computational analysis of the variant the patient’s disease (22, 23). Subsequent studies used a allele frequencies (VAF) of leukemic variants comparing
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