Editors' ChoiceCancer

Supplementing leukemia therapy

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Sci. Signal.  31 Jul 2018:
Vol. 11, Issue 541, eaau9227
DOI: 10.1126/scisignal.aau9227

Increasing the amount of dietary histidine enhances the sensitivity of leukemia xenografts in mice to methotrexate.

The drug methotrexate inhibits the activity of dihydrofolate reductase (DHFR), an enzyme that catalyzes the conversion of dihydrofolate to tetrahydrofolate (THF), the active form of the enzyme cofactor folate. Because THF is required by enzymes involved in DNA synthesis and cell proliferation, methotrexate is used to treat certain cancers; however, methotrexate also reduces the amount of THF in healthy cells, so its use is often stopped because of toxicity. Kanarek et al. used CRISPR-Cas9 to screen hematopoietic cell–derived cancer cell lines for factors that reduced their sensitivity to methotrexate. Reducing the expression of the gene encoding FTCD, an enzyme that degrades histidine in a THF-dependent manner, reduced the sensitivity of the cancer cells to methotrexate. Targeting genes encoding other enzymes in the histidine-degrading pathway led to similar results. These findings suggested that blocking the degradation of histidine spared THF in the cells, thus making them less sensitive to methotrexate. RNA-sequencing analysis of a range of cell lines showed that those with the highest expression of the gene encoding histidine ammonia lyase (HAL), which functions upstream of FTCD in the histidine degradation pathway, were the most sensitive to methotrexate. Methotrexate is often used to treat pediatric patients with acute lymphoblastic leukemia (ALL). The authors showed that patients with the highest HAL expression in ALL cells had increased survival rates compared with those of patients with the lowest HAL expression. Last, mice with tumor xenografts that were treated with low-dose methotrexate and had increased histidine in their diet showed decreased tumor size and reduced THF abundance compared with mice treated with low-dose methotrexate alone. Together, these data suggest that dietary supplementation with histidine increases histidine catabolism in cells, thus reducing the amount of available THF and sensitizing the cells to methotrexate. As Frezza discusses in commentary, these findings suggest that clinical trials should be conducted to determine whether histidine supplementation could enhance the antitumor effects of methotrexate in patients, and they also raise interesting implications for patients that take methotrexate for chronic autoimmune disorders.

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