![]() ![]() However, cancer cells can also develop nutrient dependencies through an acquired defect in de novo metabolite biosynthesis pathways. In many tumors, auxotrophies are driven by an elevated anabolic demand for metabolite building blocks, as is the case for serine ( 3), glutamine ( 4), and cysteine ( 5). One manifestation of this process is that tumor cells become more dependent on extracellular nutrient uptake for their growth and viability than do normal tissues, a process referred to as auxotrophy ( 2). Our findings reveal myo-inositol as a nutrient dependency in AML caused by the aberrant silencing of a biosynthetic enzyme.Ī consistent property of cancer cells is metabolic dysfunction, which can occur to support the energetic and biosynthetic requirements of a rapidly growing tumor ( 1). ![]() Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with IDH1/IDH2 and CEBPA mutations. 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. 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 demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. 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. An enhanced requirement for nutrients is a hallmark property of cancer cells. ![]()
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