2. Academic Validation
  3. KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs

KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs

  • Cancer Discov. 2022 Mar 1;12(3):792-811. doi: 10.1158/2159-8290.CD-20-1459.
Fangxue Yan # 1 2,  Jinyang Li # 2,  Jelena Milosevic # 3,  Ricardo Petroni 1,  Suying Liu 2 4,  Zhennan Shi 5,  Salina Yuan 2,  Janice M Reynaga 1,  Yuwei Qi 2,  Joshua Rico 1,  Sixiang Yu 2 4,  Yiman Liu 2 4 6,  Susumu Rokudai 7,  Neil Palmisiano 8,  Sara E Meyer 9,  Pamela J Sung 10,  Liling Wan 2 4 6,  Fei Lan 5,  Benjamin A Garcia 6,  Ben Z Stanger 2 11,  David B Sykes 3 12,  M Andrés Blanco 1
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 2 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 3 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts.
  • 4 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 5 Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 6 Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 7 Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.
  • 8 Department of Medical Oncology, Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
  • 9 Department of Cancer Biology, Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
  • 10 Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 11 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 12 Havard Stem Cell Institute, Cambridge, Massachusetts.
  • # Contributed equally.
PMID: 34853079 DOI: 10.1158/2159-8290.CD-20-1459
Abstract

Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the Histone Acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML.

Significance: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a "writer-reader" epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587.

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