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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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 diseases & disorders diseases & disorders > cancer > cancer types > acute myeloid leukemia organism description > animal organism description > animal > mammal organism description > animal > mammal > rodent > mouse organism description > animal > mammal > rodent diseases & disorders > cancer > cancer types
CSHL Authors:	Wei, Yiliang Huang, Yuhan Skopelitis, Damianos Iyer, Shruti Yang, Zhaolin Kramer, Melissa R. Klingbeil, Olaf Polyanskaya, Sofya Chang, Kenneth Goodwin, Sara Vakoc, Christopher R. El Demerdash, Osama Costa, Ana SH McCombie, W. Richard
Communities:	CSHL labs > Chang lab CSHL labs > McCombie lab CSHL labs > Pappin lab CSHL labs > Vakoc lab School of Biological Sciences > Publications CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	16 September 2021
Date Deposited:	23 Sep 2021 14:54
Last Modified:	09 Feb 2024 20:53
PMCID:	PMC8831445
URI:	https://repository.cshl.edu/id/eprint/40360

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