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Transcriptional silencing of ALDH2 in acute myeloid leukemia confers a dependency on Fanconi anemia proteins

Zhaolin Yang, Yiliang Wei, Xiaoli S. Wu, Shruti V. Iyer, Moonjung Jung, Emmalee R. Adelman, Olaf Klingbeil, Melissa Kramer, Osama E. Demerdash, Kenneth Chang, Sara Goodwin, Emily Hodges, W. Richard McCombie, Maria E. Figueroa, Agata Smogorzewska, Christopher R. Vakoc
doi: https://doi.org/10.1101/2020.10.23.352070
Zhaolin Yang
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Yiliang Wei
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Xiaoli S. Wu
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
2Genetics Program, Stony Brook University, Stony Brook, New York 11794, USA
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Shruti V. Iyer
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
2Genetics Program, Stony Brook University, Stony Brook, New York 11794, USA
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Moonjung Jung
3Laboratory of Genome Maintenance, The Rockefeller University, New York 10065, USA
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Emmalee R. Adelman
4Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Olaf Klingbeil
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Melissa Kramer
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Osama E. Demerdash
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Kenneth Chang
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Sara Goodwin
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Emily Hodges
5Department of Biochemistry and Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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W. Richard McCombie
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Maria E. Figueroa
4Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Agata Smogorzewska
3Laboratory of Genome Maintenance, The Rockefeller University, New York 10065, USA
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Christopher R. Vakoc
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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  • For correspondence: vakoc@cshl.edu
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Abstract

Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitin conjugation and ligation machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T (an E2) and FANCL (an E3) as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and Aldehyde Dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxic effects of endogenous aldehydes. We provide evidence that DNA hypermethylation and transcriptional silencing of ALDH2 occur in a recurrent manner in human AML patient samples, which is sufficient to confer FA pathway dependency in this disease. Taken together, our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML.

Competing Interest Statement

C.R.V. has received consulting fees from Switch, Roivant Sciences, and C4 Therapeutics, has served on the scientific advisory board of KSQ Therapeutics and Syros Pharmaceuticals, and has received research funding from Boehringer-Ingelheim during the conduct of the study.

Footnotes

  • ↵6 Lead contact

  • Key Points Dependency on the Fanconi anemia (FA) DNA interstrand crosslink repair pathway is identified in AML.

    The FA dependency is caused by silencing of Aldehyde Dehydrogenase 2, which is a recurrent epigenetic event in human AML.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 23, 2020.
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Transcriptional silencing of ALDH2 in acute myeloid leukemia confers a dependency on Fanconi anemia proteins
Zhaolin Yang, Yiliang Wei, Xiaoli S. Wu, Shruti V. Iyer, Moonjung Jung, Emmalee R. Adelman, Olaf Klingbeil, Melissa Kramer, Osama E. Demerdash, Kenneth Chang, Sara Goodwin, Emily Hodges, W. Richard McCombie, Maria E. Figueroa, Agata Smogorzewska, Christopher R. Vakoc
bioRxiv 2020.10.23.352070; doi: https://doi.org/10.1101/2020.10.23.352070
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Transcriptional silencing of ALDH2 in acute myeloid leukemia confers a dependency on Fanconi anemia proteins
Zhaolin Yang, Yiliang Wei, Xiaoli S. Wu, Shruti V. Iyer, Moonjung Jung, Emmalee R. Adelman, Olaf Klingbeil, Melissa Kramer, Osama E. Demerdash, Kenneth Chang, Sara Goodwin, Emily Hodges, W. Richard McCombie, Maria E. Figueroa, Agata Smogorzewska, Christopher R. Vakoc
bioRxiv 2020.10.23.352070; doi: https://doi.org/10.1101/2020.10.23.352070

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