Yang, Zhaolin, Wei, Yiliang, Wu, Xiaoli S, Iyer, Shruti V, Jung, Moonjung, Adelman, Emmalee R, Klingbeil, Olaf, Kramer, Melissa, Demerdash, Osama E, Chang, Kenneth, Goodwin, Sara, Hodges, Emily, McCombie, W Richard, Figueroa, Maria E, Smogorzewska, Agata, Vakoc, Christopher R (October 2020) Transcriptional silencing of ALDH2 in acute myeloid leukemia confers a dependency on Fanconi anemia proteins. bioRxiv. ISSN 2692-8205 (Submitted)
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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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > leukemia diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Chang lab CSHL labs > McCombie lab CSHL labs > Stillman lab CSHL labs > Vakoc lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 23 October 2020 |
| Date Deposited: | 24 Mar 2026 19:31 |
| Last Modified: | 24 Mar 2026 19:31 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42116 |
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