Abstract
Abstract Leukemia often displays substantial intratumor heterogeneity, comprising subpopulations of cells with different self-renewing and leukemia initiation capacities. Epigenetic mechanisms have been implicated in stem cell fate regulation during normal hematopoiesis. Although aberrant epigenetic changes have been well documented in hematological malignancies, the role epigenetic mechanisms play in governing stem-like properties, such as leukemia initiating capacity, and possible cell fate transitions between stem-like and non-stem-like leukemia subpopulations is unclear. Using next-generation sequencing and microarray technologies, we conducted an integrated analysis of DNA methylation, histone modifications and transcriptional profiles to investigate the epigenomic differences between experimentally characterized CD34-positive (CD34pos) leukemia-initiating and CD34-negative (CD34neg) non-leukemia-initiating subpopulations in a human acute myelogenous leukemia (AML) cell line. We demonstrated that multiple normal and leukemic stem cell gene signatures are significantly enriched in CD34pos leukemia initiating cells as opposed to CD34neg AML cells. We also observed concordant chromatin state transitions at the promoters of stem cell signature genes. The stem-like state of CD34pos leukemia initiating cells is also characterized by a number of genes with bivalent histone modifications at their promoters. Many genes undergoing bivalent domain resolution and transcriptional activation in CD34neg AML cells are involved in differentiation-related pathways. Most importantly, epigenomic analysis showed that treatment with epigenetic modifying agents, such as 5-aza-2'-deoxycytidine, appeared to facilitate cell fate transitions, induce marked changes in chromatin configurations, and reverse the enrichments of stem cell signatures in CD34pos leukemia-initiating cells. This provides an important molecular basis for the diminished in vitro clonogenecity and in vivo leukemogenecity of AML cells after 5-aza-2'-deoxycytidine treatment in our previous studies. Our data supports the important role of epigenetic mechanisms in underpinning cell fate and functional properties of leukemia subpopulations. The epigenetic regulation of leukemic stem-like properties might differ from that of normal hematopoietic stem cell state since the same 5-aza-2'-deoxycytidine treatment did not seem to negatively affect clonogenecity of normal hematopoietic cells. Understanding the dynamics of epigenetic state transitions between leukemia subpopulations may offer novel targets for leukemia treatment, and facilitate development of epigenetic therapy targeting leukemia initiating cells. Citation Format: Hsing-Chen Tsai, Hariharan Easwaran, Stephen B. Baylin. Epigenetic regulation of stem cell fate in leukemic subpopulations. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B27.
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