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Molecular Cancer Research
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Cancer “-omics”

5-Azacytidine Transiently Restores Dysregulated Erythroid Differentiation Gene Expression in TET2-Deficient Erythroleukemia Cells

Brian M. Reilly, Timothy Luger, Soo Park, Chan-Wang Jerry Lio, Edahí González-Avalos, Emily C. Wheeler, Minjung Lee, Laura Williamson, Tiffany Tanaka, Dinh Diep, Kun Zhang, Yun Huang, Anjana Rao and Rafael Bejar
Brian M. Reilly
1Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California.
2Moores Cancer Center, University of California San Diego, La Jolla, California.
3Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California.
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  • ORCID record for Brian M. Reilly
Timothy Luger
2Moores Cancer Center, University of California San Diego, La Jolla, California.
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Soo Park
2Moores Cancer Center, University of California San Diego, La Jolla, California.
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Chan-Wang Jerry Lio
4Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, California.
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Edahí González-Avalos
4Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, California.
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Emily C. Wheeler
1Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California.
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Minjung Lee
5Center for Epigenetics and Disease Prevention, Texas A&M University Health Science Center, Houston, Texas.
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Laura Williamson
6Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California.
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Tiffany Tanaka
2Moores Cancer Center, University of California San Diego, La Jolla, California.
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Dinh Diep
7Department of Bioengineering, University of California San Diego, La Jolla, California.
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Kun Zhang
7Department of Bioengineering, University of California San Diego, La Jolla, California.
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Yun Huang
5Center for Epigenetics and Disease Prevention, Texas A&M University Health Science Center, Houston, Texas.
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Anjana Rao
2Moores Cancer Center, University of California San Diego, La Jolla, California.
4Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, California.
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Rafael Bejar
1Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California.
2Moores Cancer Center, University of California San Diego, La Jolla, California.
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  • For correspondence: rabejar@ucsd.edu
DOI: 10.1158/1541-7786.MCR-20-0453 Published March 2021
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Abstract

DNA methyltransferase inhibitors (DNMTI) like 5-Azacytidine (5-Aza) are the only disease-modifying drugs approved for the treatment of higher-risk myelodysplastic syndromes (MDS), however less than 50% of patients respond, and there are no predictors of response with clinical utility. Somatic mutations in the DNA methylation regulating gene tet-methylcytosine dioxygenase 2 (TET2) are associated with response to DNMTIs, however the mechanisms responsible for this association remain unknown. Using bisulfite padlock probes, mRNA sequencing, and hydroxymethylcytosine pull-down sequencing at several time points throughout 5-Aza treatment, we show that TET2 loss particularly influences DNA methylation (5mC) and hydroxymethylation (5hmC) patterns at erythroid gene enhancers and is associated with downregulation of erythroid gene expression in the human erythroleukemia cell line TF-1. 5-Aza disproportionately induces expression of these down-regulated genes in TET2KO cells and this effect is related to dynamic 5mC changes at erythroid gene enhancers after 5-Aza exposure. We identified differences in remethylation kinetics after 5-Aza exposure for several types of genomic regulatory elements, with distal enhancers exhibiting longer-lasting 5mC changes than other regions. This work highlights the role of 5mC and 5hmC dynamics at distal enhancers in regulating the expression of differentiation-associated gene signatures, and sheds light on how 5-Aza may be more effective in patients harboring TET2 mutations.

Implications: TET2 loss in erythroleukemia cells induces hypermethylation and impaired expression of erythroid differentiation genes which can be specifically counteracted by 5-Azacytidine, providing a potential mechanism for the increased efficacy of 5-Aza in TET2-mutant patients with MDS.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/3/451/F1.large.jpg.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:451–64

  • Received May 18, 2020.
  • Revision received October 5, 2020.
  • Accepted November 4, 2020.
  • Published first November 10, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (3)
March 2021
Volume 19, Issue 3
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5-Azacytidine Transiently Restores Dysregulated Erythroid Differentiation Gene Expression in TET2-Deficient Erythroleukemia Cells
Brian M. Reilly, Timothy Luger, Soo Park, Chan-Wang Jerry Lio, Edahí González-Avalos, Emily C. Wheeler, Minjung Lee, Laura Williamson, Tiffany Tanaka, Dinh Diep, Kun Zhang, Yun Huang, Anjana Rao and Rafael Bejar
Mol Cancer Res March 1 2021 (19) (3) 451-464; DOI: 10.1158/1541-7786.MCR-20-0453

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5-Azacytidine Transiently Restores Dysregulated Erythroid Differentiation Gene Expression in TET2-Deficient Erythroleukemia Cells
Brian M. Reilly, Timothy Luger, Soo Park, Chan-Wang Jerry Lio, Edahí González-Avalos, Emily C. Wheeler, Minjung Lee, Laura Williamson, Tiffany Tanaka, Dinh Diep, Kun Zhang, Yun Huang, Anjana Rao and Rafael Bejar
Mol Cancer Res March 1 2021 (19) (3) 451-464; DOI: 10.1158/1541-7786.MCR-20-0453
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