Abstract BS01-1: Genetic and non-genetic mechanisms contribute to longterm clonal growth dynamics and therapy resistance

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). Two lines of evidence support the CSC model in leukemia. 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 significant independent predictors of patient survival in large clinical databases. Thus, determinants of stemness influence clinical outcome of AML across a spectrum of mutations indicating that many genetic abnormalities coalesce around stem cell properties. Second, we have carried out a series of combined genetic and functional studies of the LSC from either B-ALL or AML that point to commonalities between clonal evolution and CSC models of cancer. LSC from diagnostic patient samples were genetically diverse and reconstruction of their genetic ancestry showed that multiple LSC subclones were related through a complex branching evolutionary process. The discovery that specific genetic events influence L-IC frequency and that genetically distinct L-IC evolve through a complex evolutionary process indicates that genetic and functional heterogeneity are highly inter-related. Finally, we have also begun to study paired diagnostic (Dx) and relapse (Rx) samples and found that rare Dx subclones are chemotherapy resistant and become enriched at Rx. Collectively, our study points to the need to develop therapies that effective target all genetic subclones present in a tumor and also ensure that cells possessing stemness properties are eliminated to prevent further evolution and recurrence. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS01-1.