GSE169586
Transcriptional silencing of ALDH2 confers a dependency on Fanconi anemia proteins in acute myeloid leukemia
With domain focused CRISPR screen, we 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.  Overall design: Gene expression profiling upon CRISPR knockout or cDNA overexpression