Glioblastoma (GBM) is the most aggressive primary brain tumour, characterised by poor prognosis, high heterogeneity, and resistance to therapy. GBM patients have a median survival of 15-months post-diagnosis despite surgery, chemotherapy, and radiation1,2. A key reason for this poor prognosis is the presence of tumour ‘drivers’ — molecular alterations that fuel growth, survival, and resistance to therapy3. One such potential driver is BCL6, a well-established driver in B-cell lymphomas, and increasingly implicated in solid tumours, including GBM. BCL6 is a transcriptional repressor of various tumour suppressor and cell cycle regulator genes, and can repress cell death induced by DNA damage4. Inhibition of BCL6 in several tumour models, including GBM, has been shown to reduce tumour growth and enhance sensitivity to therapies5,6.
To elucidate whether BCL6 drives tumour formation and therapy resistance, I have engineered a genetically modified mouse cell line model (GEM-CLeM) with BCL6 overexpression either on its own, or in different GBM-relevant genetic backgrounds, such as Pten or p53 loss. In vitro data shows that BCL6 promotes cell proliferation and survival under therapeutic stress. Importantly, in vivo findings show that BCL6-overexpressing cells can form intracranial tumours in mice within 30–35 days, suggesting BCL6 alone may be sufficient to initiate tumorigenesis.
Ongoing work will assess tumour formation across other mutational backgrounds to investigate how BCL6 interacts with key GBM mutations. We are also evaluating how BCL6 influences the immune microenvironment, and tumour response to treatment. This research aims to understand how BCL6 shapes the tumour environment and whether BCL6-targeting drugs can enhance the effectiveness of current GBM treatments. These findings would support the role of BCL6 as a driver in glioma and a promising target for therapeutic strategies.