Vitamin B6 Addiction in Acute Myeloid Leukemia

Chen, C. C., Li, B., Millman, S. E., Chen, C., Li, X., Morris, J. P. Iv, Mayle, A., Ho, Y. J., Loizou, E., Liu, H., Qin, W., Shah, H., Violante, S., Cross, J. R., Lowe, S. W., Zhang, L. (January 2020) Vitamin B6 Addiction in Acute Myeloid Leukemia. Cancer Cell, 37 (1). pp. 71-84. ISSN 15356108 (ISSN) (Public Dataset)

URL: https://www.ncbi.nlm.nih.gov/pubmed/31935373
DOI: 10.1016/j.ccell.2019.12.002

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.

Item Type: Paper
Additional Information: All deep sequencing data are available from the Gene Expression Omnibus (GEO) database with the listed GEO accession numbers.
Subjects: Investigative techniques and equipment > CRISPR-Cas9
diseases & disorders > cancer > cancer types > leukemia
organs, tissues, organelles, cell types and functions > organs types and functions > metabolism
organism description > animal > mammal > rodent > mouse
CSHL Authors:
Communities: CSHL labs > Zhang lab
Depositing User: Adrian Gomez
Date: 13 January 2020
Date Deposited: 13 Jan 2020 19:34
Last Modified: 15 Jan 2020 20:52
Related URLs:
Dataset ID:
URI: https://repository.cshl.edu/id/eprint/38897

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