Researchers Discover New Potential Therapeutic Strategy to Inhibit Lymphoma Development

Researchers Discover New Potential Therapeutic Strategy to Inhibit Lymphoma Development

A new study led by researchers at the A*STAR (Agency for Science, Technology and Research) in Singapore and the National University of Singapore discovered that blocking a specific cellular machinery complex called spliceosome could arrest the development of lymphoma in mice models. The study was recently published in the renowned journal Nature and is entitled “MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphoma genesis.

Lymphoma is a form of cancer that affects the immune system, namely immune cells called lymphocytes (a type of white blood cells). There are two main types of lymphoma: non-Hodgkin’s (about 90% of the cases) and Hodgkin’s (about 10%). Patients with lymphoma may experience swelling of the lymph nodes, fever, night sweats, itching, loss of appetite, sudden weight loss and fatigue. Lymphoma is currently not a preventable cancer because the causes are unknown, but patients usually have good overall survival rates after treatment.

The MYC gene encodes a transcription factor, a protein that binds to specific DNA sequences controlling gene expression. The encoded MYC protein plays an important role in cell cycle progression and cell death. MYC is a very strong proto-oncogene, a gene that can contribute to cancer development, and it has been found to be upregulated in the majority of human cancers. This deregulation in MYC expression causes the MYC protein to be constitutively expressed, leading to high cell proliferation, reprogrammed cellular metabolism and a poor clinical prognosis. Overexpression of the MYC oncoprotein within cells makes them bind to almost all active promoters, although with different binding affinities and therefore differently modulating the expression of distinct subsets of genes.

MYC has been considered a promising target for anti-cancer therapies, however, the genes which expression is affected by MYC to potentiate tumorigenesis are still largely unknown. The goal of this study was to determine which gene sets are activated by MYC in mouse models of lymphoma.

Researchers found that during lymphomagenesis, MYC upregulates the levels of genes related to the spliceosome, which is a large molecular complex responsible for preparing messenger RNA (mRNA) molecules for protein production by removing their noncoding segments (called introns). One of these upregulated genes is PRMT5, a gene that encodes a protein essential for proper assembly of the spliceosome complex.

Using transgenic mice with only one functional PRMT5 copy (there is usually two copies of the gene), the team found that PRMT5 depletion caused several splicing defects that resulted in a reduced cancer cell viability and retarded cancer growth, leading to a delay in lymphoma development. These findings lead the team to suggest that splicing-associated genes, as is the case of PRMT5, are critical for MYC-driven tumor development.

The research team concluded that the oncogenic MYC protein plays an essential role in lymphomagenesis by safeguarding proper pre-messenger-RNA splicing. The authors suggest that PMRT5 inhibition, or other proteins related to the spliceosome, could represent a potential new therapeutic strategy to stop the development of MYC-driven cancers like lymphoma.

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