Abstract

The cellular and molecular basis for intra-tumoral heterogeneity is poorly understood. Tumor cells can be genetically diverse due to mutations and clonal evolution resulting in intra-tumoral functional heterogeneity. Often proposed as mutually exclusive, cancer stem cell (CSC) models postulate that tumors are cellular hierarchies sustained by CSC heterogeneity due to epigenetic differences (i.e. long term tumor propagation only derives from CSC ). The clinical relevance of CSC has been challenged by recent reports that some tumours may actually not adhere to a CSC model when the xenograft system is enhanced. Two lines of evidence support the CSC model in AML and B-ALL. We have recently developed gene signatures specific to either AML LSC or normal HSC and found they share a set of genes that define a common stemness program. Only these stem cell related gene signatures were found to be highly significant independent predictors of patient survival when large clinical databases were introgated. Thus, determinants of stemness influence clinical outcome of AML establishing that LSC are clinically relevant and not artifacts of xenotransplantation. Second, we have carried out a series of combined genetic and functional studies of Ph+ B-ALL leukemic initiating cells (L-IC) that point to commonalities between clonal evolution and CSC models of cancer. L-IC from diagnostic patient samples were genetically diverse and reconstruction of their genetic ancestry showed that multiple L-IC subclones were related through a complex evolutionary process that involved both linear or branching leukemic progression. The discovery that specific genetic events influence L-IC frequency and that genetically distinct L-IC evolve through a complex evolutionary process indicates that a close connection must exist between genetic and functional heterogeneity. Finally, our study points to the need to develop effective therapies to eradicate all genetic subclones in order to prevent further evolution and recurrence.