Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells

Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR–ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B , and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones. Genetic variation in leukaemia cells Genome-wide analysis of cancer cells in individual patients has revealed extensive genetic heterogeneity. Two groups have now mapped genetic homogeneity in patients with acute lymphoblastic leukaemia (ALL). Mel Greaves and colleagues obtained mutational profiles of large numbers of single cells from 60 individuals with ETV6 – RUNX1 -positive ALL, while John Dick and colleagues profile BCR-ABL1 -positive ALL. Both groups deduce the evolutionary path by which different subclones emerge during disease progression. Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insight into the heterogeneity of these functional subpopulations at the genetic level. This work has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells. Analysing human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample and the evolutionary path by which different subclones have emerged. Leukaemia-initiating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implicat