American Association for Cancer Research

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Supplementary Figures S1-S17 from SLC5A3-Dependent Myo-inositol Auxotrophy in Acute Myeloid Leukemia

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journal contribution
posted on 2023-04-03, 23:42 authored by 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

Figures S1 to S17


Leukemia and Lymphoma Society (LLS)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Pershing Square Sohn Cancer Research Alliance (PSSCRA)



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. 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

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