Dysregulation of the Core Binding Factor Complex Inhibits Differentiation and Drives Group 4 Medulloblastoma

项目总结

PROJECT SUMMARY Medulloblastoma (MB) is the most common malignant brain tumor in children. Although aggressive treatments have improved outcomes, many MB patients still die of their disease, and survivors suffer severe long-term side effects from therapy. MB comprises four subgroups—WNT, Sonic hedgehog (SHH), Group 3 and Group 4—that differ in terms of molecular alterations, clinical characteristics and outcomes. We have some understanding of the molecular mechanisms underlying WNT, SHH and Group 3 tumors, but the pathways that drive Group 4 medulloblastoma (G4MB), the most prevalent form of the disease, remain a mystery. The lack of progress on G4MB has been due to a poor understanding of the genes, cells and processes leading to the disease. Recently, we identified a putative cell of origin for G4MB and a polyprotein complex whose members are mutated in the majority of G4 tumors. Our preliminary studies suggest that G4MB arises from a population of bipotential progenitor cells in the rhombic lip that gives rise to glutamatergic neurons, including unipolar brush cells (UBCs) and granule neurons (GNs). The fate of these progenitors is controlled by the Core Binding Factor (CBFA) complex, which contains transcriptional co-repressors, transcription factors, histone demethylases and histone methyltransferases. During early development, this complex maintains cells in a progenitor state. Later, when the complex is inactivated, cells undergo differentiation into GNs and UBCs. Alterations that prevent inactivation of this complex are predicted to prevent differentiation and maintain cells in a progenitor state. Importantly, we found that genetic alterations in members of this complex are among the most common driver events in G4MB. We hypothesize that mutations in the CBFA complex derail normal differentiation and constitute the core mutational route to G4MB, and that targeting this complex will improve outcomes for G4MB patients. To test this hypothesis, we will determine how the CBFA complex regulates differentiation and tumorigenesis, test whether alteration of the complex can drive G4MB tumorigenesis, and determine whether targeting the CBFA complex promotes differentiation and inhibits G4MB. Collectively, these studies will address fundamental questions regarding the origin and underlying mechanisms driving G4MB tumorigenesis, and probe newly revealed vulnerabilities to develop novel approaches to therapy for this devastating disease.