Healthy cells keep their use of vitamin B6 under control. You could say that they are casual or functional users. Leukemic cells, however, are full-blown addicts. The difference between being strung out on vitamin B6 and managing it responsibly can come down to a single gene—the gene that expresses an enzyme called PDXK. If this enzyme or its cohorts in the vitamin B6 pathway could be targeted by inhibitory or disruptive drugs, new treatment strategies could be developed against acute myeloid leukemia (AML).
Vitamin B6 is crucial to cell metabolism, producing energy and other resources important for cell growth. In a healthy cell, the PDXK enzyme manages the activity of B6, making sure that the vitamin does the job when needed. Because normal cells don’t divide all the time, the PDXK enzyme isn’t always pushing the B6 vitamin to be active.
It’s a different dynamic in leukemic cells, which divide more frequently than normal cells. According to a new study led by researchers from Cold Spring Harbor Laboratory (CSHL) and Memorial Sloan Kettering Cancer Center (MSKCC), leukemic cells are always pushing B6 activity and proliferating at a high level. Leukemic cells spread so quickly they outpace most treatments, which is why only one-third of AML patients survive five years after diagnosis.
The CSHL/MSKCC scientists, led by CSHL fellow Lingbo Zhang, PhD, decided to figure out how AML can achieve such rapid growth. They looked closely at the genes of the disease’s cancerous white blood cells. “We found more than 230 genes that are very active in leukemic cells,” Zhang said, “and then we tested them, one by one.”
A description of this work appeared January 13 in the journal Cancer Cell, in an article titled, “Vitamin B6 Addiction in Acute Myeloid Leukemia.”
“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 AML-selective dependency,” the article’s authors indicated. “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.”
This work suggests that AML could be slowed by limiting the ability of leukemic cells to manipulate PDXK. It’s an approach to attacking cancer without harming healthy cells, which need the B6 vitamin to survive.
Using CRISPR gene-editing technology, Zhang’s lab shut down the activity of each of the 230 suspect genes to see if their absence would stop the cancer cells from proliferating. Among the hundreds of genes they tested, one pattern emerged: The gene that produces PDXK proved most important for the growth of the cancer.
Scott Lowe, a former CSHL fellow and currently the chair of the cancer biology and genetics program at MSKCC, said “while the action of certain vitamins has previously been linked to cancer, the specific links between vitamin B6 identified here were unexpected.” What this shows is that leukemic cells are addicted to vitamin B6. “You can call it a vulnerability of the cancer,” he stressed.
“PDXK disruption reduced intracellular concentrations of key metabolites needed for cell division,” the article’s authors noted. “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.”
Zhang cautioned that these findings do not mean that cancer patients would necessarily benefit from reduced intake of B6 as part of their diet. After all, B6 is necessary for the survival of healthy cells. Nonetheless, the findings still point to “a pharmacologically actionable dependency in AML.” They show that cancer cells take advantage of the PDXK enzyme to increase B6 vitamin activity. This increased activity fuels AML growth.
Zhang and his colleagues say the next step is to develop a drug that specifically blocks leukemia from activating the PDXK enzyme. By manipulating the way the enzyme manages the activity of B6, a drug could slow or even stop the growth of cancerous cells without the profound side effects that would result from completely eliminating B6 from healthy cells. With the help of medicinal chemists, the team is now exploring this route.