Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (4), 568-587
- https://doi.org/10.1158/2159-8290.cd-19-1059
Abstract
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. See related article by E. Waanders et al.Keywords
Other Versions
Funding Information
- Princess Margaret Cancer Centre Foundation Ontario Institute for Cancer Research
- NCI (P30 CA021765, R35 CA197695)
- Natural Sciences and Engineering Research Council
- Dutch Cancer Society (KUN2012-5366)
This publication has 64 references indexed in Scilit:
- Signatures of mutational processes in human cancerNature, 2013
- Acute B lymphoblastic leukaemia‐propagating cells are present at high frequency in diverse lymphoblast populationsEMBO Molecular Medicine, 2012
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapseThe Journal of Experimental Medicine, 2011
- CREBBP mutations in relapsed acute lymphoblastic leukaemiaNature, 2011
- Bambino: a variant detector and alignment viewer for next-generation sequencing data in the SAM/BAM formatBioinformatics, 2011
- Densely Interconnected Transcriptional Circuits Control Cell States in Human HematopoiesisCell, 2011
- Deletion ofIKZF1and Prognosis in Acute Lymphoblastic LeukemiaThe New England Journal of Medicine, 2009
- Reference alignment of SNP microarray signals for copy number analysis of tumorsBioinformatics, 2008
- Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic LeukemiaScience, 2008