John E. Dick PhD FRS
Senior Scientist and Canada Research Chair,
Princess Margaret Cancer Centre, University Health Network.
Professor, Dept of Molecular Genetics, University of Toronto.
Director, Translational Research Initiative in Leukemia, Ontario Institute for Cancer Research.

Tracking the arc of AML and B-ALL from the cell of origin to the origin of relapse in a single blood sample

Individual cancer cells exhibit functional heterogeneity of many cancer hallmarks including the capacity for sustaining long-term clonal maintenance, a stemness property involving self-renewal. Our studies established that only rare AML cells possessed such leukemia stem cell (LSC) properties and that AML is a cellular hierarchy. LSC were found to be highly relevant to human disease as gene signatures specific to LSC were much more predictive of patient response to therapy and overall survival compared to the bulk non-LSC AML cells. We have recently shown that the genetic and hierarchy models of heterogeneity are not mutually exclusive as often posited, but highly integrated. Through sequencing of purified populations of normal blood cells, AML cells, and xenografts from paired diagnosis/relapse AML samples, we tracked the full arc of leukemia development in humans: from the cell of origin (an HSC) that acquires the first genetic mutation; to pre-leukemic clonal expansion of HSC; the generation of genetically diverse LSC; and finally to the cellular origin of relapse (rare LSC subclones) within the diagnosis sample. Similar studies have been undertaken in B-ALL where relapse-fated subclones were proven to be partially resistant to clinically used drugs. By showing that pre-existing LSC survive therapy and cause relapse, the key role that stemness plays in human cancer is evident. The ability to track the cellular origin of relapse will enable biomarker development leading to improved methods for disease management and monitoring in AML. Finally, the existence of clonally expanded pre-leukemic HSPC in the diagnosis blood sample of many AML samples predicted that it should be possible to identify individuals who are at risk for progressing to AML long before AML develops. We have undertaken genotyping studies of normal individuals who have enrolled in the large cohort EPIC who eventually developed AML and compared them to the enrollment sample of others who never progressed to AML. We have found a clear signature that is able to predict with high accuracy those individuals who have age related clonal hematopoiesis (ARCH) who progress to AML, almost 10 years prior to AML development. This is distinct from individuals who have benign ARCH who never progress. These new findings offer the potential for future intervention to permit AML prevention trials.