Abstract
Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor. No effective curative therapy is currently available and no therapeutic advances have been made in several decades. BMI-1 is a member of the multimeric protein complex Polycomb repressor complex 1. It is overexpressed in a number of diseases and malignancies and has been implicated in self-renewal of normal and cancer cells, and in DNA damage signaling. The role of BMI-1 in DIPG is largely unknown. Here, we show that BMI-1 is overexpressed in DIPG patient tissue samples and in patient-derived cancer stem cells independent of H3K27 mutation status. BMI-1 downregulation leads to the inhibition of DIPG patient-derived stem cell proliferation, cell cycle signaling, self-renewal, telomerase expression and activity, causes increased apoptosis, and suppresses DIPG cell invasion. Moreover, targeted inhibition of BMI-1 sensitizes DIPG cells to radiomimetic drug-induced DNA damage. Together, our data validate BMI-1 as a potential therapeutic target to treat children with DIPG regardless of H3 mutation status. *S. S Kumar, S. Sengupta and K. Lee contributed equally to this work.
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