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Drug addiction mutations unveil a methylation ceiling in EZH2-mutant lymphoma

View ORCID ProfileHui Si Kwok, View ORCID ProfileAllyson M. Freedy, View ORCID ProfileAllison P. Siegenfeld, View ORCID ProfileJulia W. Morriss, View ORCID ProfileAmanda L. Waterbury, View ORCID ProfileStephen M. Kissler, View ORCID ProfileBrian B. Liau
doi: https://doi.org/10.1101/2022.04.04.486977
Hui Si Kwok
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Allyson M. Freedy
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Allison P. Siegenfeld
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Julia W. Morriss
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Amanda L. Waterbury
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Stephen M. Kissler
3Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
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Brian B. Liau
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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  • For correspondence: liau@chemistry.harvard.edu
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Abstract

Cancer mutations in Polycomb Repressive Complex 2 (PRC2) drive aberrant epigenetic states. Although therapies inhibiting the PRC2 enzymatic component EZH2 are FDA-approved, oncogene-specific dependencies remain to be discovered. Here, we identify mutations that confer both resistance and drug addiction to PRC2 inhibitors in EZH2-mutant lymphoma, resulting in cancer cells that paradoxically depend on drug for survival. Drug addiction is mediated by hypermorphic mutations in the CXC domain of EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Drug removal leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Activating EZH2 cancer mutations establish an epigenetic state precariously close to this ceiling, which we show can be breached by inhibition of SETD2, a PRC2 antagonist, to block lymphoma growth. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.

Competing Interest Statement

Brian Liau is on the Scientific Advisory Board of H3 Biomedicine.

Footnotes

  • ↵† Co-first authors

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 05, 2022.
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Drug addiction mutations unveil a methylation ceiling in EZH2-mutant lymphoma
Hui Si Kwok, Allyson M. Freedy, Allison P. Siegenfeld, Julia W. Morriss, Amanda L. Waterbury, Stephen M. Kissler, Brian B. Liau
bioRxiv 2022.04.04.486977; doi: https://doi.org/10.1101/2022.04.04.486977
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Drug addiction mutations unveil a methylation ceiling in EZH2-mutant lymphoma
Hui Si Kwok, Allyson M. Freedy, Allison P. Siegenfeld, Julia W. Morriss, Amanda L. Waterbury, Stephen M. Kissler, Brian B. Liau
bioRxiv 2022.04.04.486977; doi: https://doi.org/10.1101/2022.04.04.486977

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