The crossroads of clonal evolution, differentiation hierarchy and ontogeny in leukemia development

Transformative technologies to sequence tumor genomes at large scale and single-cell resolution have exposed the repertoire of genetic alterations that are present in leukemia genomes, the timing of their acquisition and patterns of their co-occurrence. In parallel, single-cell multi-omics technologies are allowing us to map the differentiation paths and hierarchical structures of malignant cells and giving us a glimpse into hematopoietic development in prenatal life. We propose that interrogating how the genetic evolution, differentiation hierarchy and ontogeny of malignant myeloid cells intersect with each other, using new experimental systems and multimodal technologies, will fuel the next generation of research breakthroughs.