The Crossroads of Clonal Evolution, Differentiation Hierarchy, and Ontogeny in Leukemia Development
Christopher M. Sturgeon, Elvin Wagenblast, Franco Izzo, Eirini P. Papapetrou
Abstract
Abstract 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 multiomics 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. Significance: In recent years, remarkable technological advances have illuminated aspects of the pathogenesis of myeloid malignancies—yet outcomes for patients with these devastating diseases have not significantly improved. We posit that a synthesized view of the three dimensions through which hematopoietic cells transit during their healthy and diseased life—clonal evolution, stem cell hierarchy, and ontogeny—promises high yields in new insights into disease pathogenesis and new therapeutic avenues.