LAUSR

Cells from the same tumor can exhibit significant variation in their genomes, epigenomes, and transcriptomes, resulting in distinct cellular phenotypes. Such intra-tumor heterogeneity is a substrate for tumor evolution, e.g. generating cell clones with a growth advantage or chemotherapy resistance, and thus poses a key challenge in cancer therapy. Epigenetic heterogeneity is increasingly recognized as a critical feature of tumors that endows them with biological variability and hence options for subsets of cells to manifest selective growth and survival advantages. However, the source of epigenetic heterogeneity and its potential link to cancer-associated mutations remains unknown. Herein, we have addressed this topic in the context of acute myeloid leukemia, a disease that is usually fatal but that nonetheless is characterized by a relative paucity of somatic mutations. We hypothesize that genetic lesions drive epigenetic heterogeneity, which disrupts gene expression in tumor cell clones, and leads to fitness differences that can be selected for as the cancer evolves. We test the hypothesis in the following three questions about epigenetic heterogeneity. First, what is the source of epigenetic heterogeneity in cancer? We show for the first time that epigenetic clonality is directly linked to specific mutations. Surprisingly, epigenetic alleles tend to occur in specific patterns in patients with particular driver mutations, suggesting that leukemia oncoproteins can destabilize specific loci that are linked to hematopoietic stem cell transcription factors. However, we also identify a sizeable cohort of patients with mutations that do not drive epigenetic allele patterning. Instead these patients manifest extensive epigenetic clonal diversity that apparently evolves in a stochastic manner through natural selection, and which is linked with inferior clinical outcomes. Second, is epigenetic allele diversity a manifestation of transformed cells, or does it precede and hence potentially contribute to malignant transformation? Here we show that development of epigenetic clonality actually precedes prior to transformation and so is demonstrably caused by AML mutations. Notably, mutations in IDH are a potent inducer of epigenetic allele diversity. Third, is epigenetic clonality reversible with epigenetic therapy agents? Remarkably, we find that epigenetic targeted therapy can reverse both epigenetic allele diversity and the transcriptional deregulation that it causes. This may explain why it is that epigenetic therapy can prime tumors for treatment with chemotherapy drugs, by eliminating options for subpopulations of cancer cells to escape. In sum, we show for the first time that epigenetic clonality is directly linked to specific mutations, and epigenetic allele diversity precede and potentially contribute to malignant transformation. Furthermore, epigenetic clonality reversible with epigenetic therapy agents. Together, these findings support the rationale for future studies to rigorously track epigenetic heterogeneity over time in AML patients at relevant time points, and to determine if epiallele reduction associates with improved therapeutic response. Citation Format: Sheng Li. Somatic mutations drive specific but reversible epigenetic heterogeneity states in AML [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG04.