London Calling 2023: Single-cell long-read RNA sequencing reveals complex heterogeneity in leukaemia

While introduction of novel targeted inhibitors has markedly altered the therapeutic options for treating patients with blood cancers, relapses due to acquired resistance after initial response remain a major problem. To delineate drug resistance, we applied a novel single-cell omics approach on samples from patients with progressive leukaemia who failed therapy with a targeted agent. Combining short-read with long-read targeted and whole-transcriptome sequencing identified mutations and alternative transcripts in specific sub-clones of the tumour at relapse. Thus, our single-cell integration of short-read and full-length RNA-seq provides novel insights into how complex tumour heterogeneity evolves upon acquisition of drug resistance.