Study points to CD73 as novel therapeutic target in acute myeloid leukemia
A recent study from the Porse group at the Finsen Laboratory, DanStem and BRIC, shows that the cancer-protective and -targetable CD73-gene is upregulated in a type of leukemia, indicating a potential novel therapy.
"Anti-CD73 treatment is gaining popularity in solid cancers with many clinical trials. This study could attract attention to the possibility of targeting CD73 also in leukemia – paving the way for new precision medicine in a field with a high level of unmet medical need", Janus Schou Jakobsen, Porse Group
The researcher studied the so-called CEBPA-mutant leukemia, where the CEBPA protein has a leukemia-specific mutated form. Normally, the protein CEBPA is important for regulating the development of specific blood cells from stem cells. In the new study published in Science Advances, the leukemia-mutated CEBPA was shown to upregulate the CD73 gene. The researchers used an in-house developed technique to find all the places in the genome where a leukemia-specific mutated form, but not the healthy form, of CEBPA binds. This pinpointed a piece of DNA that regulated CD73 in the leukemic mouse model. Notably, patients with leukemia also displayed upregulation of CD73 and activity of a corresponding piece of regulatory DNA.
CD73 holds potential as a specific target for precision medicine
In the CEBPA-mutant leukemia, the researchers found that CD73 upregulation resulted in an internal signalling in the leukemic cells, resulting in more aggressive growth when tested in cell cultures. In CEBPA-mutant leukemic mice, blocking CD73 signalling with a combination of antibodies and small molecule inhibitors increased their survival substantially. Using a combination of molecular techniques and advanced computational analyses, the researchers further demonstrated that CD73 expression and the internal leukemia cell signalling was specific to samples from patients with CEBPA-mutated leukemia and not found in other leukemia types. Together, this points to CD73 as a very realistic and specific novel therapeutic target in this subtype of acute myeloid leukemia.
Supported by the Danish Cancer Society, the Danish Association for Cancer Research and the Novo Nordisk Foundation.
Jakobsen, J.S., Laursen, L.G., Schuster, M.B., Pundhir, S., Schoof, E., Ge, Y., d’Altri, T., Vitting-Seerup, K., Rapin, N., Gentil, C., Jendholm, J., Theilgaard-Mönch, K., Reckzeh, K., Bullinger, L., Döhner, K., Hokland, P., Fitzgibbon, J., Porse, B.T. (2019) Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML. Science Advances, 5, eaaw4304, doi: 10.1126/sciadv.aaw4304.