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

Abstract

Disease recurrence causes signifi cant 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, identifi ed 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.

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

“…Potential limitations to the use of targeted drugs in pediatric T-ALL include clonal heterogeneity of the disease, resulting in only partial elimination of leukemia cells upon therapy. Therefore, resistant clones may be selected and survive under the selective pressure of treatment (8,9). Similar resistance mechanisms have already been demonstrated for conventional chemotherapeutics such as the glucocorticoid-selected NR3C1 mutations (10)(11)(12) and the 6-mercaptopurine-selected NT5C2 mutations in chemoresistant relapsed ALL (11,13).…”

Pediatric acute lymphoblastic leukemia

“…[80][81][82][83] At diagnosis, minor relapse-initiating subclones can exhibit inherent resistance to chemotherapy, even before secondary mutation acquisition. 84 Other relapse-specific mutations in PRPS1, PRSP2, NT5C2, or MSH6, each influencing thiopurine metabolism, may emerge only during therapy, being driven by selective therapeutic pressure. 81,83,85,86 These mutations confer chemotherapy resistance and might have implications for disease monitoring and therapeutic decisions.…”

Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies

“…Resistance to chemotherapy can be pre-existing (intrinsic) or drug-induced (acquired) ( Figure 1) [16]. Up to half of cancers exhibit intrinsic resistance, while 50% of the remaining half will acquire resistance as a result of treatment [17], even though deeper sequencing strategies at diagnosis might reveal that many presumed acquired resistances indeed was present in subclones already at diagnosis as demonstrated for leukaemia [18]. Both types of resistance are the result of altered drug metabolism and/or modified drug targets (reviewed in [15]).…”