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SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia


Wei YYiliang , Huang YHYu-Han , Skopelitis DSDamianos S , Iyer SVShruti V , Costa ASHAna S H , Yang ZZhaolin , Kramer MMelissa , Adelman EREmmalee R , Klingbeil OOlaf , Demerdash OEOsama E , Polyanskaya SASofya A , Chang KKenneth , Goodwin SSara , Hodges EEmily , McCombie WRW Richard , Figueroa MEMaria E , Vakoc CRChristopher R . Cancer discovery. 2021 09 16; ().


An enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a dependency in this disease. We demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. The commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate limiting enzyme for myo-inositol biosynthesis, inositol-3-phosphate synthase 1. We use gain- and loss-of-function experiments to reveal a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hyper-methylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with IDH1/IDH2 and CEBPA mutations. Our findings reveal myo-inositol as a nutrient dependency in AML caused by the aberrant silencing of a biosynthetic enzyme.