Abstract
Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis brain tumor with no effective curative therapy. We previously identified BMI-1 as a potential therapeutic target in DIPG*. We have shown that BMI-1 is highly expressed in DIPG tumors and patient-derived cells regardless of histone subtype. In the present study, we used PTC596, a potent BMI-1 modulator recently entered into clinical trials. PTC596 treatment results in post-translational modification of BMI-1, affecting its downstream target H2AK119 mono-ubiquitination levels. BMI-1 has been shown to be one of the early proteins recruited to DNA damage sites during the process of DNA damage response (DDR). In DIPG cells treated with PTC596, we observed time and concentration dependent increase in both γH2AX phosphorylation levels and foci formation, indicating DNA double strand breaks (DSBs). Cell cycle analysis, cleaved caspase-3 and γH2AX staining showed a sequence of events leading to apoptosis of DIPG cells treated with PTC596. Moreover, the kinetics of DDR was impaired in DIPG cells treated with ionizing radiation (IR) in combination with PTC596. Both the foci formation and resolution were delayed resulting in further reduction in cell viability compared with either treatment alone. Our results suggest that PTC596-induced modulation of BMI-1 sensitizes DIPG cells to IR. This is the first report providing evidence supporting the effectiveness of IR in combination with BMI-1 modulation to treat DIPG. *Kumar, S.S. et al. BMI-1 is a Potential Therapeutic Target in Diffuse Intrinsic Pontine Glioma. Oncotarget 2017.