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Somatic Mutations Drive Specific, but Reversible, Epigenetic Heterogeneity States in AML

Sheng Li, Xiaowen Chen, Jiahui Wang, Cem Meydan, Jacob L. Glass, Alan H. Shih, Ruud Delwel, Ross L. Levine, Christopher E. Mason and Ari M. Melnick
Sheng Li
1The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
2The Jackson Laboratory Cancer Center, Bar Harbor, Maine.
3The Department of Genetics and Genomic Sciences, The University of Connecticut Health Center, Farmington, Connecticut.
4Department of Computer Science and Engineering, University of Connecticut, Storrs, Connecticut.
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  • ORCID record for Sheng Li
  • For correspondence: amm2014@med.cornell.edu sheng.li@jax.org
Xiaowen Chen
1The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
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Jiahui Wang
1The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
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Cem Meydan
5Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.
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Jacob L. Glass
6Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Alan H. Shih
7Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.
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Ruud Delwel
8Department of Hematology, Erasmus University Medical Center and Oncode Institute, Rotterdam, the Netherlands.
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Ross L. Levine
9Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Christopher E. Mason
5Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.
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Ari M. Melnick
10Division of Hematology/Oncology, Weill Cornell Medicine, New York, New York.
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  • For correspondence: amm2014@med.cornell.edu sheng.li@jax.org
DOI: 10.1158/2159-8290.CD-19-0897 Published December 2020
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Abstract

Epigenetic allele diversity is linked to inferior prognosis in acute myeloid leukemia (AML). However, the source of epiallele heterogeneity in AML is unknown. Herein we analyzed epiallele diversity in a genetically and clinically annotated AML cohort. Notably, AML driver mutations linked to transcription factors and favorable outcome are associated with epigenetic destabilization in a defined set of susceptible loci. In contrast, AML subtypes linked to inferior prognosis manifest greater abundance and highly stochastic epiallele patterning. We report an epiallele outcome classifier supporting the link between epigenetic diversity and treatment failure. Mouse models with TET2 or IDH2 mutations show that epiallele diversity is especially strongly induced by IDH mutations, precedes transformation to AML, and is enhanced by cooperation between somatic mutations. Furthermore, epiallele complexity was partially reversed by epigenetic therapies in AML driven by TET2/IDH2, suggesting that epigenetic therapy might function in part by reducing population complexity and fitness of AMLs.

Significance: We show for the first time that epigenetic clonality is directly linked to specific mutations and that epigenetic allele diversity precedes and potentially contributes to malignant transformation. Furthermore, epigenetic clonality is reversible with epigenetic therapy agents.

This article is highlighted in the In This Issue feature, p. 1775

Footnotes

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

  • Cancer Discov 2020;10:1934–49

  • Received August 1, 2019.
  • Revision received July 9, 2020.
  • Accepted September 11, 2020.
  • Published first September 16, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (12)
December 2020
Volume 10, Issue 12
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Somatic Mutations Drive Specific, but Reversible, Epigenetic Heterogeneity States in AML
Sheng Li, Xiaowen Chen, Jiahui Wang, Cem Meydan, Jacob L. Glass, Alan H. Shih, Ruud Delwel, Ross L. Levine, Christopher E. Mason and Ari M. Melnick
Cancer Discov December 1 2020 (10) (12) 1934-1949; DOI: 10.1158/2159-8290.CD-19-0897

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Somatic Mutations Drive Specific, but Reversible, Epigenetic Heterogeneity States in AML
Sheng Li, Xiaowen Chen, Jiahui Wang, Cem Meydan, Jacob L. Glass, Alan H. Shih, Ruud Delwel, Ross L. Levine, Christopher E. Mason and Ari M. Melnick
Cancer Discov December 1 2020 (10) (12) 1934-1949; DOI: 10.1158/2159-8290.CD-19-0897
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