SLC5A3-Dependent Myo-inositol Auxotrophy in Acute Myeloid Leukemia.

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 hypermethylation 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. SIGNIFICANCE: 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.This article is highlighted in the In This Issue feature, p. 275. ©2021 The Authors; Published by the American Association for Cancer Research.

Citation

Yiliang Wei, Yu-Han Huang, Damianos S Skopelitis, Shruti V Iyer, Ana S H Costa, Zhaolin Yang, Melissa Kramer, Emmalee R Adelman, Olaf Klingbeil, Osama E Demerdash, Sofya A Polyanskaya, Kenneth Chang, Sara Goodwin, Emily Hodges, W Richard McCombie, Maria E Figueroa, Christopher R Vakoc. SLC5A3-Dependent Myo-inositol Auxotrophy in Acute Myeloid Leukemia. Cancer discovery. 2022 Feb;12(2):450-467

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PMID: 34531253

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