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

Yang, Zhaolin, Wu, Xiaoli S, Wei, Yiliang, Polyanskaya, Sofya A, Iyer, Shruti V, Jung, Moonjung, Lach, Francis P, Adelman, Emmalee R, Klingbeil, Olaf, Milazzo, Joseph P, Kramer, Melissa, Demerdash, Osama E, Chang, Kenneth, Goodwin, Sara, Hodges, Emily, McCombie, W Richard, Figueroa, Maria E, Smogorzewska, Agata, Vakoc, Christopher R (April 2021) Transcriptional silencing of ALDH2 confers a dependency on Fanconi anemia proteins in acute myeloid leukemia. Cancer Discovery. ISSN 2159-8274

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 ubiquitination machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T and FANCL 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 genotoxicity of endogenous aldehydes. We show that DNA hypermethylation and silencing of ALDH2 occur in a recurrent manner in human AML, which is sufficient to confer FA pathway dependency. Our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA methylation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene silencing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function diseases & disorders > cancer > cancer types > leukemia organs, tissues, organelles, cell types and functions
CSHL Authors:	Yang, Zhaolin Wu, Xiaoli Wei, Yiliang Polyanskaya, Sofya Iyer, Shruti Klingbeil, Olaf Milazzo, Joseph Kramer, Melissa R. Chang, Kenneth Goodwin, Sara Hodges, Emily Vakoc, Christopher R. McCombie, W. Richard
Communities:	CSHL labs > Chang lab CSHL labs > McCombie lab CSHL labs > Vakoc lab School of Biological Sciences > Publications CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Shared Resources > Sequencing Technology & Analysis Service
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	23 April 2021
Date Deposited:	28 Apr 2021 14:21
Last Modified:	13 Feb 2024 19:39
PMCID:	PMC8419016
URI:	https://repository.cshl.edu/id/eprint/39939

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