MutaSeq reveals the transcriptomic consequences of clonal evolution in acute myeloid leukemia

The step-wise acquisition of genetic abnormalities in cancer is thought to represent a major driver of disease initiation, relapse and therapy resistance. Acute myeloid leukemia (AML) represents a prime example of an aggressive cancer that develops in a multi-step manner from multipotent hematopoietic progenitors via pre-leukemic intermediates to leukemic cells. While bulk and single-cell genomics provide powerful tools to study the phylogenetics of cancer evolution, the specific transcriptomic changes induced by the accumulation of mutations remain largely unexplored. Here, we introduce MutaSeq, a combined single-cell genetic and transcriptomics platform for the identification of molecular consequences of cancer evolution. Through in-depth profiling of an AML patient, we demonstrate that MutaSeq is capable of: (1) fine-mapping clonal and developmental hierarchies (2) quantifying the ability of leukemic and pre-leukemic clones to give rise to mature lineages and (3) identifying surface markers and mRNA transcripts specific to pre-leukemic, leukemic, and residual healthy cells. The experimental and analytical approach presented here is broadly applicable to other types of cancer, and can help identify targets for eradicating both pre-cancerous and cancerous reservoirs of relapse.