New research directions in medulloblastoma.

INTRODUCTION: Medulloblastoma is the most common type of pediatric malignant brain tumor where the most important amount of clinical and radiological data has been accumulated in recent years. This has led to its sophistication in the management of these patients with a clear benefit for the patients. Long-term outcome and sequelae have been described and their causes well understood such as preventive measures which can now be implemented. MATERIAL AND METHODS: This review paper does not attempt to make a systematic review of the literature in the field of research regarding medulloblastoma. It rather reflects more the opinion of a pediatric oncological team involved for a long time in this type of research. Therefore, a relevant literature review was carried out and selected by the senior author. RESULTS: Medulloblastoma is no longer a single entity but a group of at least 4 different diseases with a specific oncogenesis. In addition, biomarkers for prognosis have emerged to complement the known clinico-radiological risk factors. If this biological classification has allowed to modulate the therapeutic strategies, it has not yet brought many new drugs (except for the Sonic Hedgehog inhibitors) in the armamentarium against medulloblastomas. Consequently, some high-risk tumors remain difficult to cure. Combining data on oncogenesis and prognostic biomarkers will allow to define risk groups more specifically. New targeted therapies that are more effective and less toxic are desperately needed. Alternatively, it is also justified to study preventive measures to decrease the sequelae of the tumor and its treatments. From the therapeutic point of view, we scarcely know the biological determinants of chemosensitivity and radiosensitivity, as well as those associated with metastases which are indeed invaluable for tailored therapeutic strategies. CONCLUSION: If some genetic causes of medulloblastoma are known, the occurrence of the disease is largely unexplained for the others, justifying more research in this area. If genomics (and to a lesser extent epigenomics) of these neoplasms has been well studied, little is known on their proteomics and on the regulatory networks involved in the biological behavior of these tumor cells. New models are developed to test these aspects.

Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation.

The nucleolar Arf protein has been shown to regulate cell cycle through both p53-dependent and -independent pathways. In addition to the well-characterized Arf-mdm2-p53 pathway, several partners of Arf have recently been described that could participate in alternative regulation process. Among those is the nucleolar protein B23/NPM, involved in the sequential maturation of rRNA. p19ARF can interact with B23/NPM in high molecular complexes and partially inhibit the cleavage of the 32S rRNA, whereas the human p14ARF protein has been shown to participate in the degradation of NPM/B23 by the proteasome. These data led to define Arf as a negative regulator of ribosomal RNA maturation. Our recent finding that the human p14ARF protein was able to specifically interact with the rRNA promoter in a p53-independent context, led us to analyse in vitro and in vivo the consequences of this interaction. Luciferase assay and pulse-chase experiments demonstrated that the rRNA transcription was strongly reduced upon p14ARF overexpression. Investigations on potential interactions between p14ARF and the transcription machinery proteins demonstrated that the upstream binding factor (UBF), required for the initiation of the transcriptional complex, was a new partner of the p14ARF protein. We next examined the phosphorylation status of UBF as UBF phosphorylation is required to recruit on the promoter factors involved in the transcriptional complex. Upon p14ARF overexpression, UBF was found hypophosphorylated, thus unable to efficiently recruit the transcription complex. Taken together, these data define a new p53-independent pathway that could regulate cell cycle through the negative control of rRNA transcription.