Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML Journal Article

   

Authors:	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.; Levine, R. L.; Carroll, M.; Melnick, A. M.
Article Title:	Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML
Abstract:	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. 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.This article is highlighted in the In This Issue feature, p. 813. ©2019 American Association for Cancer Research.
Journal Title:	Cancer Discovery
Volume:	9
Issue:	7
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2019-07-01
Start Page:	872
End Page:	889
Language:	English
DOI:	10.1158/2159-8290.Cd-19-0106
PUBMED:	31076479
PROVIDER:	scopus
PMCID:	PMC6606333
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069265625&doi=10.1158%2f2159-8290.CD-19-0106&partnerID=40&md5=dc19639300c7bb5d783aba45f6efe89e
Notes:	Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/150112