Détails sur le projet
Description
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.
Statut | Terminé |
---|---|
Date de début/de fin réelle | 4/4/11 → 8/31/23 |
Financement
- National Cancer Institute: 643 914,00 $ US
Keywords
- Genética
- Biología molecular
Empreinte numérique
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