Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia

To better understand clonal and transcriptional adaptations after relapse in AML patients, we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA-sequencing on the same samples, yielding 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes were significantly correlated with genetic changes. However, transcriptional adaptation sometimes occurred independently, suggesting that clonal evolution does not represent all relevant biological changes. In three cases, we identified cells at diagnosis that likely seeded the relapse. Finally, this data revealed a conserved relapse-enriched leukemic cell state bearing markers of stemness, quiescence, and adhesion.