Studying genetic factors influencing DNA damage and repair during ageing: drug treatments and models of JAK/STAT pathway-related blood cancers

The ubiquity of DNA damage from both natural and artificial sources poses a constant challenge to all living organisms. This research aims to better understand the processes that modulate DNA damage and how they contribute to disease and ageing, with a particular focus on the JAK/STAT signalling pathway and its inhibition by methotrexate (MTX) in Drosophila melanogaster models. The JAK/STAT pathway plays a pivotal role in cellular growth, development, and immune responses, and its dysregulation is implicated in various malignancies and disorders, including myeloproliferative neoplasms (MPNs). MTX, initially developed over seven decades ago as an anti-folate chemotherapeutic agent, is currently a World Health Organization-listed 'essential medicine' and serves as a first-line treatment for autoimmune and inflammatory conditions such as rheumatoid arthritis and psoriasis. Recent research in the Zeidler lab has identified MTX as an inhibitor of the JAK/STAT pathway, which is already targeted by other treatments for rheumatoid arthritis. This study reveals that low-dose MTX does not induce significant DNA damage in Drosophila melanogaster and may even extend lifespan and healthspan, suggesting potential applications beyond its traditional use in treating inflammatory diseases.
While high doses of MTX are associated with toxicity and DNA damage, low doses appear to be less harmful and may offer protective effects, opening new avenues for safer and more effective treatments for various diseases. Other findings demonstrates that folinic acid can mitigate the toxic effects of MTX in Drosophila. Low doses of MTX were found to inhibit JAK/STAT signalling in the gut of adult Drosophila, aligning with previous findings in human cell lines and suggesting a dose-dependent cellular stress response at higher concentrations. The preliminary data from next generation sequencing reveals that low concentrations of MTX (≤100 nM) did not induce inheritable mutations in the X chromosome DNA of Drosophila, supporting earlier findings that such concentrations do not cause DNA damage or affect biological processes like eclosion and wing serration. This observation contrasts with the genotoxic effects observed at higher MTX concentrations (>1 µM), which negatively influenced various biological processes and induced DNA damage. The study calls for further research to explore the transgenerational effects of MTX, and may even help with a new discovery, given the limitations of the current study's sample size and genomic scope.