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 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 essent...

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Bibliographic Details
Published in:Cancer discovery 2022-02, Vol.12 (2), p.450-467
Main Authors: Wei, Yiliang, Huang, Yu-Han, Skopelitis, Damianos S, Iyer, Shruti V, Costa, Ana S H, Yang, Zhaolin, Kramer, Melissa, Adelman, Emmalee R, Klingbeil, Olaf, Demerdash, Osama E, Polyanskaya, Sofya A, Chang, Kenneth, Goodwin, Sara, Hodges, Emily, McCombie, W Richard, Figueroa, Maria E, Vakoc, Christopher R
Format: Article
Language:English
Subjects:
Animals
Developmental Biology
Heat-Shock Proteins - genetics
Humans
Inositol - biosynthesis
Leukemia, Myeloid, Acute - drug therapy
Mice
Symporters - genetics
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Summary:An enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an 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 , 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 and in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of occur in a recurrent manner in human AML patient samples, in association with and 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. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-20-1849