Evolution of Human BCR-ABL1 lymphoblastic Leukaemia-Initiating Cells.

Abstract 1023

Many tumour types are composed of genetically diverse cells, however little is known of 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 acute lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct subclones. Reconstruction of the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multiclonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, while 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/CDKN2B, and poor patient outcome. Our findings link clonal diversity with function and underscore the importance of developing therapies that eradicate all subclones.