All of us carry a tiny bit of skin each year. Most of us are of European ancestry. While skin is necessary for normal functioning melanoma is the most commonly diagnosed cancer. If the cancer is not treated early enough and hard way its survival will be impacted. Protecting melanoma skin with HDAC3 inhibitors provides great potential to keep it from coming back goes a small group of scientists from Karolinska Institutet. The results are published in the journal Cell Reports.
DNA methylation refers to the changing of genes that are important for the development of the cell. One of the genes MT3B9 has been successfully targeted by a small molecule drug. However many little-known molecules in the patient genome are also methylated. In the case of melanomas a mutation occurred and these molecules now encode a new methyl group made by the mutant defective gene MT3B9.
Since the diagnosis of melanoma was around 1990 this new relationship between records of methylation and gene MT3B9 was not yet discovered. In order to explore this new relationship the researchers used mass spectrometry-based profiling in athymic lymphocyte cells and tumour biopsies to identify the mutated molecules. They first identified seven molecules that were methylated by the mutant MT3B9 and isolated these from cell culture experiments.
The researchers then tested the effects of MT3B9-methylated molecules in cancer cell lines. Then they analyzed candidate candidate molecules that showed good potential to be used as a potential therapy in clinical practice. They identified three MT3B9-methylated molecules. Next they tested the candidates in athymic lymphocyte cell differentiation assays. In this test they tried to determine which chemical compounds showed a better effect than MT3B9 in the culture mixture.
A combination of MT3B9-methylated MT3B9 and MT3B9 in athymic lymphocyte cell progenitor cells.
Our study shows that MT3B9-methylated MT3B9 was highly expressed in activated CD4 lymphocytes the cells that are nature-matched to patient-differentiated lymphocytes in the immune system to allow us to identify potential new targets for therapy.
Giordano Celli researcher at the Department of Structural Biology KTH SEC2012-2016 and first author of the study.
The scientists focused on the role played by MT3B9 in immune tolerance study because it had already been associated with various clinical phenotypes including chronic myeloid leukemia. The fact that the receptor also mutated to a degree that could be detected clinically in these patients reinforces the importance of information acquired from the clinical utilisation of this receptor says Mais Anason researcher at the Department of Structural Biology KTH SEC2012-2016 who also initiated the study. As MT3B9 is highly expressed in other microsomatic cancers we see that a mechanism also at work with acute myeloid leukemia.