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)
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: | [error in script] |
| Communities: | CSHL labs > Zhang lab CSHL Cancer Center Program > Gene Regulation and Inheritance Program |
| Depositing User: | Adrian Gomez |
| Date: | 13 January 2020 |
| Date Deposited: | 13 Jan 2020 19:34 |
| Last Modified: | 01 Dec 2020 15:10 |
| PMCID: | PMC7197326 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/38897 |
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