Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML

Duy, C., Teater, M., Garrett-Bakelman, F. E., Lee, T. C., Meydan, C., Glass, J. L., Li, M., Hellmuth, J. C., Mohammad, H. P., Smitheman, K. N., Shih, A. H., Abdel-Wahab, O., Tallman, M. S., Guzman, M. L., Muench, D., Grimes, H. L., Roboz, G. J., Kruger, R. G., Creasy, C. L., Paietta, E. M., … Melnick, A. M. (2019). Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML. Cancer discovery, 9(7), 872–889. https://doi.org/10.1158/2159-8290.CD-19-0106

Disruption of epigenetic regulation is a hallmark of acute myeloid leukemia (AML), but epigenetic therapy is complicated by the complexity of the epigenome. Herein, we developed a long-term primary AML ex vivo platform to determine whether targeting different epigenetic layers with 5-azacytidine and LSD1 inhibitors would yield improved efficacy. This combination was most effective in TET2mut AML, where it extinguished leukemia stem cells and particularly induced genes with both LSD1-bound enhancers and cytosine-methylated promoters. Functional studies indicated that derepression of genes such as GATA2 contributes to drug efficacy. Mechanistically, combination therapy increased enhancer–promoter looping and chromatin-activating marks at the GATA2 locus. CRISPRi of the LSD1-bound enhancer in patient-derived TET2mut AML was associated with dampening of therapeutic GATA2 induction. TET2 knockdown in human hematopoietic stem/progenitor cells induced loss of enhancer 5-hydroxymethylation and facilitated LSD1-mediated enhancer inactivation. Our data provide a basis for rational targeting of cooperating aberrant promoter and enhancer epigenetic marks driven by mutant epigenetic modifiers.

Journal: Cancer Discovery PMID: 31076479 DOI: 10.1158/2159-8290.CD-19-0106