TMOD-17. CONVERGENCE OF BMI1 AND CHD7 ON ERK SIGNALLING IN MEDULLOBLASTOMA

Abstract

Medulloblastoma is the most common malignant brain tumour of childhood, and a common cause of pediatric morbidity and mortality. Medulloblastomas have been dissected into four distinct molecular subgroups (WNT, SHH, Group 3, Group 4) with divergent clinical and biological profiles. The Polycomb group protein Bmi1 is upregulated in a variety of cancers, has a positive correlation with clinical grade/stage and poor prognosis and it is a highly druggable molecule. Bmi1 is overexpressed across all MB subgroups; the growth of SHH and Group 4 MB is dependent on Bmi1 expression. Genome wide in vivo insertional mutagenesis (T2Onc2) driven by the Sleeping Beauty (SB11) transposase in glutamatergic progenitor cells engineered to over-express Bmi1 results in medulloblastoma formation, while neither Bmi1 over-expression nor T2Onc2 transposition alone drives tumorigenesis. On the Bmi1 over-expressing background, we observe frequent T2Onc2 inactivating insertions in the chromatin remodelling factor Chd7 (Chromodomain helicase DNA binding factor 7), suggesting that Bmi1 overexpression and Chd7 loss of function cooperate to induce medulloblastoma. High expression of BMI1 in combination with low expression of CHD7 is associated with a poor prognosis in human medulloblastoma. Loss of function mutations of CHD7are observed in medulloblastoma, particularly in Group 4. CHD7 knockdown in patient-derived Group 4 medulloblastoma cells led to increased proliferation and increased expression of markers of undifferentiated and highly proliferative progenitor cells both in vitro and in xenografts. Importantly, we show the BMI1-dependency of the phenotype observed upon CHD7 knockdown and the molecular convergence on ERK signalling. These finding extend the current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis and raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of medulloblastoma with low expression level of CHD7.