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

Cihangir Duy, Matt Teater, Francine E. Garrett-Bakelman, Tak C. Lee, Cem Meydan, Jacob L. Glass, Meng Li, Johannes C. Hellmuth, Helai P. Mohammad, Kimberly N. Smitheman, Alan H. Shih, Omar Abdel-Wahab, Martin S. Tallman, Monica L. Guzman, David Muench, H. Leighton Grimes, Gail J. Roboz, Ryan G. Kruger, Caretha L. Creasy, Elisabeth M. Paietta & 3 others Ross L. Levine, Martin Carroll, Ari M. Melnick

Research output: Contribution to journalArticle

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 mut locus. CRISPRi of the LSD1-bound enhancer in patient-derived TET2 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.

Original languageEnglish (US)
Pages (from-to)872-889
Number of pages18
JournalCancer discovery
Volume9
Issue number7
DOIs
StatePublished - Jul 1 2019

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Acute Myeloid Leukemia
Epigenomics
Therapeutics
Hematopoietic Stem Cells
Genes
Azacitidine
Cytosine
Gene Silencing
Chromatin
Leukemia
Stem Cells
Mutation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology

Cite this

Duy, C., Teater, M., Garrett-Bakelman, F. E., Lee, T. C., Meydan, C., Glass, J. L., ... 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

Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML. / Duy, 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; Grimes, H. Leighton; Roboz, Gail J.; Kruger, Ryan G.; Creasy, Caretha L.; Paietta, Elisabeth M.; Levine, Ross L.; Carroll, Martin; Melnick, Ari M.

In: Cancer discovery, Vol. 9, No. 7, 01.07.2019, p. 872-889.

Research output: Contribution to journalArticle

Duy, C, Teater, M, Garrett-Bakelman, FE, Lee, TC, Meydan, C, Glass, JL, Li, M, Hellmuth, JC, Mohammad, HP, Smitheman, KN, Shih, AH, Abdel-Wahab, O, Tallman, MS, Guzman, ML, Muench, D, Grimes, HL, Roboz, GJ, Kruger, RG, Creasy, CL, Paietta, EM, Levine, RL, Carroll, M & Melnick, AM 2019, 'Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML', Cancer discovery, vol. 9, no. 7, pp. 872-889. https://doi.org/10.1158/2159-8290.CD-19-0106
Duy, 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 ; Grimes, H. Leighton ; Roboz, Gail J. ; Kruger, Ryan G. ; Creasy, Caretha L. ; Paietta, Elisabeth M. ; Levine, Ross L. ; Carroll, Martin ; Melnick, Ari M. / Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML. In: Cancer discovery. 2019 ; Vol. 9, No. 7. pp. 872-889.
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AU - Glass, Jacob L.

AU - Li, Meng

AU - Hellmuth, Johannes C.

AU - Mohammad, Helai P.

AU - Smitheman, Kimberly N.

AU - Shih, Alan H.

AU - Abdel-Wahab, Omar

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AU - Guzman, Monica L.

AU - Muench, David

AU - Grimes, H. Leighton

AU - Roboz, Gail J.

AU - Kruger, Ryan G.

AU - Creasy, Caretha L.

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AU - Levine, Ross L.

AU - Carroll, Martin

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