Senescence Induced by BMI1 Inhibition is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

Diffuse Intrinsic pontine glioma is an incurable brain tumor of childhood characterized by histone mutations at lysine 27 which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. We performed a combined RNAi and chemical screen targeting epigenetic regulatory genes and identified the polycomb (PcG) repressive complex 1, component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy was enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 results in decreased cell self-renewal and attenuation of tumor growth due to induction of senescence. Prolong BMI1 inhibition induces a senescence associated secretory phenotype which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to synergistically attenuate tumor growth in vivo.