Synapse - Vitamin B6 addiction in acute myeloid leukemia

Vitamin B6 addiction in acute myeloid leukemia Journal Article

Authors:	Chen, C. C.; Li, B.; Millman, S. E.; Chen, C.; Li, X.; Morris, J. P. 4th; Mayle, A.; Ho, Y. J.; Loizou, E.; Liu, H.; Qin, W.; Shah, H.; Violante, S.; Cross, J. R.; Lowe, S. W.; Zhang, L.
Article Title:	Vitamin B6 addiction in acute myeloid leukemia
Abstract:	In a CRISPR/Cas9 functional screen targeting metabolic enzymes, Chen et al. identify PDXK, which produces pyridoxal phosphate (PLP) from vitamin B6, as an AML dependency. PLP-dependent enzymes ODC1 and GOT2 support AML proliferation. Blockade of the vitamin B6 metabolic pathway exhibits anti-leukemic activity. © 2019 Elsevier Inc. 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. © 2019 Elsevier Inc.
Keywords:	controlled study; nonhuman; cell proliferation; animal cell; mouse; gene targeting; cell cycle progression; gene expression; embryo; animal experiment; animal model; in vivo study; cell differentiation; leukemia cell; leukemogenesis; down regulation; pyridoxal kinase; therapeutic target; functional genomics; rna sequence; antileukemic activity; acute myeloid leukemia; pyridoxine; gene knockdown; priority journal; article; plp-dependent enzyme; crispr-cas9 system; abt-199/venetoclax; b cell lymphoma-2; crispr/cas9 functional genomics; pyridoxal phosphate; selective metabolic dependency; vitamin b6
Journal Title:	Cancer Cell
Volume:	37
Issue:	1
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2020-01-13
Start Page:	71
End Page:	84.e7
Language:	English
DOI:	10.1016/j.ccell.2019.12.002
PROVIDER:	scopus
PUBMED:	31935373
PMCID:	PMC7197326
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85077368059&doi=10.1016%2fj.ccell.2019.12.002&partnerID=40&md5=eb629c797296e5c79dcebcd9f7d4be0e
Notes:	Article -- Source: Scopus