| Popis: |
Medulloblastomas (MB) is the most common malignant brain tumour of childhood, and a common cause of pediatric morbidity and mortality. MB have recently 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, as Bmi1 knockdown results in reduced tumour growth and invasion. 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 MB 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 MB. High expression of BMI1 in combination with low expression of CHD7 is associated with a poor prognosis in human MB. Loss of function mutations of CHD7 are observed in MB, particularly in Group 4. Lentiviral mediated Chd7 knockdown (Chd7 kd) in patient-derived Group 4 MB cells led to increased proliferation and increased expression of markers of undifferentiated and highly proliferative progenitor cells both in vitro and in vivo. Importantly, we show the Bmi1-dependency of the phenotype observed upon Chd7 knockdown, as concomitant knock down of Bmi1 neutralised both increased proliferation and reversion to an undifferentiated state. We describe a novel molecular convergence between Bmi1 and Chd7 in the initiation and maintenance of MB. These finding raise the possibility that Bmi1 antagonists may be particularly indicated in a subgroup of MB with low expression level of Chd7. |
