TitleRational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML.
Publication TypeJournal Article
Year of Publication2019
AuthorsDuy, Cihangir, Teater Matt, Garrett-Bakelman Francine E., Lee Tak C., Meydan Cem, Glass Jacob L., Li Meng, Hellmuth Johannes C., Mohammad Helai P., Smitheman Kimberly N., Shih Alan H., Abdel-Wahab Omar, Tallman Martin S., Guzman Monica L., Muench David, H Grimes Leighton, Roboz Gail J., Kruger Ryan G., Creasy Caretha L., Paietta Elisabeth M., Levine Ross L., Carroll Martin, and Melnick Ari M.
JournalCancer Discov
Date Published2019 Jul
KeywordsAnimals, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Dioxygenases, DNA (Cytosine-5-)-Methyltransferase 1, DNA Methylation, DNA-Binding Proteins, Enhancer Elements, Genetic, Epigenome, GATA2 Transcription Factor, Genes, Tumor Suppressor, Histone Demethylases, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Neoplastic Stem Cells, Promoter Regions, Genetic, Proto-Oncogene Proteins, Random Allocation, Tumor Cells, Cultured, Xenograft Model Antitumor Assays

<p>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 platform to determine whether targeting different epigenetic layers with 5-azacytidine and LSD1 inhibitors would yield improved efficacy. This combination was most effective in 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 contributes to drug efficacy. Mechanistically, combination therapy increased enhancer-promoter looping and chromatin-activating marks at the locus. CRISPRi of the LSD1-bound enhancer in patient-derived AML was associated with dampening of therapeutic induction. 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. SIGNIFICANCE: Somatic mutations of genes encoding epigenetic modifiers are a hallmark of AML and potentially disrupt many components of the epigenome. Our study targets two different epigenetic layers at promoters and enhancers that cooperate to aberrant gene silencing, downstream of the actions of a mutant epigenetic regulator..</p>

Alternate JournalCancer Discov
PubMed ID31076479
PubMed Central IDPMC6606333
Grant ListR01 CA198089 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
U24 CA196172 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
U10 CA180820 / CA / NCI NIH HHS / United States
UG1 CA233332 / CA / NCI NIH HHS / United States
U10 CA180827 / CA / NCI NIH HHS / United States
UG1 CA233290 / CA / NCI NIH HHS / United States
K08 CA169055 / CA / NCI NIH HHS / United States