SLC5A3-Dependent Myo-inositol Auxotrophy in Acute Myeloid Leukemia

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 common-ality 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. 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. Block-ing the function of this solute carrier may have therapeutic potential in an epigenetically defined subset of AML.

Original languageEnglish (US)
Pages (from-to)450-467
Number of pages18
JournalCancer discovery
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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