RT Journal Article SR Electronic T1 Transcriptional silencing of ALDH2 in acute myeloid leukemia confers a dependency on Fanconi anemia proteins JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.10.23.352070 DO 10.1101/2020.10.23.352070 A1 Yang, Zhaolin A1 Wei, Yiliang A1 Wu, Xiaoli S. A1 Iyer, Shruti V. A1 Jung, Moonjung A1 Adelman, Emmalee R. A1 Klingbeil, Olaf A1 Kramer, Melissa A1 Demerdash, Osama E. A1 Chang, Kenneth A1 Goodwin, Sara A1 Hodges, Emily A1 McCombie, W. Richard A1 Figueroa, Maria E. A1 Smogorzewska, Agata A1 Vakoc, Christopher R. YR 2020 UL http://biorxiv.org/content/early/2020/10/23/2020.10.23.352070.abstract AB 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 StatementC.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.