In vivo isogenic modelling unveils a TP53-mediated relapse phenotype in T-cell acute lymphoblastic leukemia

Abstract

Many patients with T-cell acute lymphoblastic leukemia (T-ALL) relapse into a treatment-resistant disease. The mechanisms driving relapse remain largely elusive, in part due to the lack of faithful experimental models. Here, we leveraged patient-derived xenograft (PDX) pairs generated from diagnosis and relapse T-ALLs to functionally address the cellular mechanisms driving TP53-altered relapse. Beyond inter-T-ALL variability, comparative analyses revealed a unique, cell-intrinsic relapse phenotype that includes greater leukemia-initiating capacity and that can be conferred to diagnosis cells by TP53 silencing. Transcriptomic profiling linked the relapse phenotype to deregulated OXPHOS metabolism and MYC signaling. Integration of single-cell profilings uncovered TP53-wildtype cell populations at diagnosis expressing a relapse profile, possibly reflecting a pre-existing modulation of TP53 signaling. These cells sequentially evolved towards biallelic TP53 inactivation at relapse. Collectively, our findings support a model in which T-ALL relapses emerge from a selected pre-existing transcriptional state characterized by deregulated metabolism that favors subsequent TP53 inactivation.