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In vivo genetic screen identifies a SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia

Publication

Date: 22nd December 2020 | Source: BioRxiv

Authors: Yiliang Wei, Shruti V. Iyer, Ana S. H. Costa, Zhaolin Yang, Melissa Kramer, Emmalee R. Adelman, Olaf Klingbeil, Osama E. Demerdash, Sofya Polyanskaya, Kenneth Chang, Sara Goodwin, Emily Hodges, W. Richard McCombie, Maria E. Figueroa, Christopher R. Vakoc.

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.

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