Abstract IA10: The role of stem cells in the origin of relapse in acute leukemia
Authors: Dick John E. 
Published: May 2016

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 created due to epigenetic programs that are sustained by CSC. I will focus on three lines of evidence showing these models are highly integrated. Gene signatures specific to either AML LSC or normal HSC are highly similar and define a common stemness program. Compared to non-stem cell transcriptional programs, only stem cell signatures were significant independent predictors of patient survival in 4 large clinical databases of &gt;1000 samples. Thus, determinants of stemness influence clinical outcome of AML across a spectrum of mutations indicating that many genetic abnormalities coalesce around stem cell properties. Secondly, 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 and specific genetic events influence L-IC frequency. Also study of paired diagnostic (Dx) and relapse (Rx) samples are revealing that individual subclones possess distinct functional growth properties and that rare Dx subclones are chemotherapy resistant and become enriched at Rx. Thus the clonal evolution models are highly relevant in cancer but need to be extended to adopt the concept that CSC are subject to clonal evolutionary forces. Finally, the combined genetic and functional analysis of AML is revealing fundamental insights into the cell of origin, nature and biological consequences of initiating lesions and order of subsequent mutations; concepts that demonstrate how highly integrated the CSC and genetic evolution models must be. Highly purified hematopoietic stem cells (HSC), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3a mutations (DNMT3amut) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3amut-bearing HSC exhibited multilineage repopulation advantage over non-mutated HSC in xenografts, establishing their identity as pre-leukemic-HSC (preL-HSC). preL-HSC were found in remission samples indicating that they survive chemotherapy. Thus DNMT3amut arises early in AML evolution, likely in HSC, leading to a clonally expanded pool of preL-HSC from which AML evolves. For therapy to be more effective, our findings indicate that each genetic subclones must be targeted and that any cells that possess stemness properties, whether they are LSC or ancestral preL-HSC, must also be eradicated.

Citation Format: John E. Dick. The role of stem cells in the origin of relapse in acute leukemia. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA10.