Relapse-fated latent diagnosis subclones in acute B lineage leukemia are drug tolerant and possess distinct metabolic programs

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 RuschYing 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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

68 Citaten (Scopus)


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. 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 strategies to identify and target clinically relevant subclones before further evolution toward relapse.

Originele taal-2Engels
Pagina's (van-tot)568-587
Aantal pagina's20
TijdschriftCancer Discovery
Nummer van het tijdschrift4
StatusGepubliceerd - apr. 2020


Duik in de onderzoeksthema's van 'Relapse-fated latent diagnosis subclones in acute B lineage leukemia are drug tolerant and possess distinct metabolic programs'. Samen vormen ze een unieke vingerafdruk.

Citeer dit