19 July 2021

Spanish scientists have revealed a new approach which could potentially delay the onset of follicular lymphoma.

One in six people with follicular lymphoma has mutations in the RRAGC gene for the protein RagC. RagC is part of the mTOR nutrient signalling pathway which controls metabolic activity and cell growth.

Researchers, led by Dr Alejo Efeyan of the Metabolism and Cell Signalling Group at the Spanish National Cancer Research Centre, carried out studies with mice to investigate the impact of partially blocking the RagC protein. They found that this approach safely delays the onset of follicular lymphoma. Details appeared in the journal Cell Reports last week.

Previously, the team discovered that mutations in the RRAGC gene cause follicular lymphoma tumours by preventing it the RagC protein from switching off. “This was the first evidence of the tumour-promoting activity of RagC, and of the set of genes that inform mTOR of the presence of nutrients for growth,” the authors write.

This time they looked at reducing the activity of RagC. As predicted, inhibiting it removed the metabolic ability of tumour cells to use nutrients. But its full inhibition cannot continue because it is essential to normal functioning of the body.

So, Dr Efeyan and colleagues introduced a specific mutation into the gene to only partially decrease its activity.

Co-author Dr Ana Ortega-Molina says: “Surprisingly, this decrease in RagC activity in mice caused a significant delay in the progression of follicular lymphomas, which was accompanied by a block in the activation of B lymphocytes.

“Moreover, this decrease had no harmful side effects or a negative impact on longevity and life expectancy, which has been linked for years to the mTOR pathway. Mice show weights, glucose levels, neuromuscular coordination, skin thickness and liver damage normal for their age.”

The team add that other diseases in which B cells are altered, such as autoimmune diseases, could be tackled in a similar way with selective inhibitors of the RagC pathway.


Source:

Ortega-Molina A, Lebrero-Fernández C, Sanz A, Deleyto-Seldas N, Plata-Gómez AB, Menéndez C, Graña-Castro O, Caleiras E, Efeyan A. (2021) “Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs.” Cell Reports, doi: 10.1016/j.celrep.2021.109372.

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