Vitamin B6 Addiction in Acute Myeloid Leukemia.
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Vitamin B6 Addiction in Acute Myeloid Leukemia.

Chen, Chi-Chao;Li, Bo;Millman, Scott E;Chen, Cynthia;Li, Xiang;Morris, John P;Mayle, Allison;Ho, Yu-Jui;Loizou, Evangelia;Liu, Hui;Qin, Weige;Shah, Hardik;Violante, Sara;Cross, Justin R;Lowe, Scott W;Zhang, Lingbo;
cancer cell 2020 Vol. 37 pp. 71-84.e7
248
chen2020vitamincancer

Abstract

Cancer cells rely on altered metabolism to support abnormal proliferation. We performed a CRISPR/Cas9 functional genomic screen targeting metabolic enzymes and identified PDXK-an enzyme that produces pyridoxal phosphate (PLP) from vitamin B6-as an acute myeloid leukemia (AML)-selective dependency. PDXK kinase activity is required for PLP production and AML cell proliferation, and pharmacological blockade of the vitamin B6 pathway at both PDXK and PLP levels recapitulated PDXK disruption effects. PDXK disruption reduced intracellular concentrations of key metabolites needed for cell division. Furthermore, disruption of PLP-dependent enzymes ODC1 or GOT2 selectively inhibited AML cell proliferation and their downstream products partially rescued PDXK disruption induced proliferation blockage. Our work identifies the vitamin B6 pathway as a pharmacologically actionable dependency in AML.

Keywords

therapeutic target pyridoxal phosphate acute myeloid leukemia abt-199/venetoclax b cell lymphoma-2 crispr/cas9 functional genomics plp-dependent enzyme pyridoxal kinase selective metabolic dependency vitamin b6

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S1535-6108(19)30572-0

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