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Combined MYC and TP53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease [gene expression]

ABSTRACT: We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53–MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. There are currently no effective therapies for children with relapsed medulloblastoma. While clinical and biological features of the disease at diagnosis are increasingly well understood, biopsy is rarely performed at relapse and few biological data are available to guide more effective treatments. Here, we show that medulloblastomas develop altered biology at relapse which is predictive of disease course and cannot be detected at diagnosis. We have discovered the emergence of P53–MYC interactions at relapse, as biomarkers of clinically aggressive relapsed disease, which can be modelled and targeted therapeutically in genetically-engineered mice. These data provide clear precedent for the incorporation of biopsy at relapse into routine clinical practice, to direct palliative care and the development of improved treatment strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE62625 | GEO | 2015/04/23

SECONDARY ACCESSION(S): PRJNA264566

REPOSITORIES: GEO

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Project description:We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53–MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. There are currently no effective therapies for children with relapsed medulloblastoma. While clinical and biological features of the disease at diagnosis are increasingly well understood, biopsy is rarely performed at relapse and few biological data are available to guide more effective treatments. Here, we show that medulloblastomas develop altered biology at relapse which is predictive of disease course and cannot be detected at diagnosis. We have discovered the emergence of P53–MYC interactions at relapse, as biomarkers of clinically aggressive relapsed disease, which can be modelled and targeted therapeutically in genetically-engineered mice. These data provide clear precedent for the incorporation of biopsy at relapse into routine clinical practice, to direct palliative care and the development of improved treatment strategies. mouse model expression profiles from various mouse Medulloblastoma models MYCN/MYC overexpressing with/without p53 Mutations were compared to human MB expression profiles using Non-negative Matrix Factorization projection in order to sub-type the mouse models

Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumorâ??s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma. ChIP-Seq experiments for Miz1, c-Myc and NMyc from murine medulloblastoma material. Either sorted tumor cells (Miz1 and c-Myc) or spheres from tumor cells (Miz1 and NMyc) were used. Input-samples were sequenced as controls. RNA-Seq from G3 medulloblastomas after restoration of Atoh1 expression.

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Combined MYC and TP53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease [gene expression]

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