Wei, Yiliang, Iyer, Shruti V, Costa, Ana SH, Yang, Zhaolin, Kramer, Melissa, Adelman, Emmalee R, Klingbeil, Olaf, Demerdash, Osama E, Polyanskaya, Sofya, Chang, Kenneth, Goodwin, Sara, Hodges, Emily, McCombie, W Richard, Figueroa, Maria E, Vakoc, Christopher R (December 2020) In vivo genetic screen identifies a SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia. bioRxiv. ISSN 2692-8205 (Submitted)
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Abstract
An enhanced requirement for extracellular nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy for evaluating dependencies in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a unique vulnerability in this disease. In accord with this transport function, we demonstrate that the SLC5A3 dependency reflects a myo-inositol auxotrophy in AML. Importantly, the commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate limiting enzyme for myoinositol biosynthesis, inositol-3-phosphate synthase 1. We used gain- and loss-of-function experiments to demonstrate 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 the presence of IDH1/IDH2 and CEBPA mutations. Collectively, our findings reveal myo-inositol auxotrophy as a novel form of metabolic dysregulation in AML, which is caused by the aberrant silencing of a biosynthetic enzyme. Statement of significance Here, 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > acute myeloid leukemia diseases & disorders > cancer > cancer types > leukemia diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Chang lab CSHL labs > McCombie lab CSHL labs > Stillman lab CSHL labs > Vakoc lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 22 December 2020 |
| Date Deposited: | 24 Mar 2026 19:38 |
| Last Modified: | 24 Mar 2026 19:38 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42117 |
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