American Association for Cancer Research
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Supplementary Table S7 from Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs

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posted on 2023-04-03, 22:21 authored by Stephanie M. Dobson, Laura García-Prat, Robert J. Vanner, Jeffrey Wintersinger, Esmé Waanders, Zhaohui Gu, Jessica McLeod, Olga I. Gan, Ildiko Grandal, Debbie Payne-Turner, Michael N. Edmonson, Xiaotu Ma, Yiping Fan, Veronique Voisin, Michelle Chan-Seng-Yue, Stephanie Z. Xie, Mohsen Hosseini, Sagi Abelson, Pankaj Gupta, Michael Rusch, Ying Shao, Scott R. Olsen, Geoffrey Neale, Steven M. Chan, Gary Bader, John Easton, Cynthia J. Guidos, Jayne S. Danska, Jinghui Zhang, Mark D. Minden, Quaid Morris, Charles G. Mullighan, John E. Dick

RNA-sequencing, pathway enrichment (GSEA) reports and GSVA results (including gene list HSC vs B) of PDX and paired patient samples


Princess Margaret Cancer Centre Foundation

Ontario Institute for Cancer Research


Natural Sciences and Engineering Research Council

Dutch Cancer Society



Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic 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 sequencing, 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. 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 strategies to identify and target clinically relevant subclones before further evolution toward relapse.See related video: related article by E. Waanders et al.