SLC5A3-Dependent Myo-inositol Auxotrophy in Acute Myeloid Leukemia.

Autor:	Wei Y; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Huang YH; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Skopelitis DS; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Iyer SV; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Stony Brook University, Stony Brook, New York., Costa ASH; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Yang Z; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Kramer M; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Adelman ER; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida., Klingbeil O; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Demerdash OE; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Polyanskaya SA; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Chang K; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Goodwin S; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Hodges E; Department of Biochemistry and Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, Tennessee., McCombie WR; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Figueroa ME; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida., Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. vakoc@cshl.edu.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2022 Feb; Vol. 12 (2), pp. 450-467. Date of Electronic Publication: 2021 Sep 16.
DOI:	10.1158/2159-8290.CD-20-1849
Abstrakt:	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 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. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically defined subset of AML. This article is highlighted in the In This Issue feature, p. 275 . (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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