SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia.

Wei, Yiliang, Huang, Yu-Han, Skopelitis, Damianos S, Iyer, Shruti V, Costa, Ana SH, 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 (September 2021) SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia. Cancer Discovery. candisc.1849.2020-candisc.1849.2020. ISSN 2159-8274

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URL: https://www.ncbi.nlm.nih.gov/pubmed/34531253
DOI: 10.1158/2159-8290.CD-20-1849

Abstract

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 hyper-methylation 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.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > acute myeloid leukemia
CSHL Authors:
Communities: CSHL labs > Chang lab
CSHL labs > McCombie lab
CSHL labs > Pappin lab
CSHL labs > Vakoc lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 16 September 2021
Date Deposited: 23 Sep 2021 14:54
Last Modified: 23 Sep 2021 14:54
URI: https://repository.cshl.edu/id/eprint/40360

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