An enhanced requirement for extracellular nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy for evaluating dependencies in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a unique vulnerability in this disease. In accord with this transport function, we demonstrate that the SLC5A3 dependency reflects a myo-inositol auxotrophy in AML. Importantly, the commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate limiting enzyme for myoinositol biosynthesis, inositol-3-phosphate synthase 1. We used gain- and loss-of-function experiments to demonstrate a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with the presence of IDH1/IDH2 and CEBPA mutations. Collectively, our findings reveal myo-inositol auxotrophy as a novel form of metabolic dysregulation in AML, which is caused by the aberrant silencing of a biosynthetic enzyme.Statement of significanceHere, we show how epigenetic silencing can provoke a nutrient dependency in AML by exploiting a synthetic lethality relationship between biosynthesis and transport of myo-inositol. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically-defined subset of AML.
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