Cancer Cell 37, 71–84 (2020)

Different cancer cell types utilize specific metabolic pathways to promote their growth and proliferation. To identify metabolic dependencies required for the growth of acute myeloid leukemia (AML), Chen et al. performed a CRISPR–Cas9 screen revealing that pyridoxal kinase (PDXK), an enzyme that mediates the production of pyridoxal phosphate (PLP) from vitamin B6, was selectively depleted in leukemia cancer cells and was specifically required for AML cell proliferation. Metabolomic profiling of PDXK-depleted AML cells showed decreased nucleotide and glycolytic metabolites, confirming PLP as an essential co-factor for enzymes involved in nucleic acid and lipid metabolism. Given that the loss of PDXK activity reduced PLP levels in all cell types but only impacted AML proliferation, the authors performed a focused CRISPR–Cas9 screen and identified eight PLP-dependent enzymes required for AML proliferation. In particular, they found that ODC1, a decarboxylase that promotes putrescine production, and GOT2, a transaminase that generates aspartate and nucleotides, were essential for regulating leukemic proliferation. Finally, treatment of a mouse leukemic model with a PDXK inhibitor reduced leukemic cell growth. Overall, these findings will inspire improved drug discovery efforts targeting PDXK to treat AML.