ARF suppression by MYC but not MYCN confers increased malignancy of Group 3 medulloblastoma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139240 | GEO | 2022/12/21
REPOSITORIES: GEO
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Project description:BACKGROUND Focal high-level amplifications of MYC define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains less clear. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in a large cohort of 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). METHODS Twenty-one MYCN-MB with MYCN amplication and 56 MYCN-MB were respectively examined using either gene expression profiling and array-CGH, or immunohistochemical analysis and FISH. All 67 tumors were further subject to mutational analyses. Semi non-negative matrix factorization–based and unsupervised hierarchical clustering methods were used to identify biological groups. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. RESULTS Transcriptomic analysis of this large cohort of MYCN-MBs demonstrated a significant enrichment of MYCN-MB in the SHH and group D variants. Further substantiating this biological dichotomy of MYCN-MB, respective group affiliations were also accompanied by variant-specific cytogenetic aberrations including deletion of 9q in the SHH variant, and gain of 7q and isochromosome 17q/17q gain in MYCN-MBs clustering with group D tumors. Among clinically relevant variables, SHH subtype and 10q loss for Non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. CONCLUSION We demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be excluded before a patient is enrolled into a clinical trial using a Smoothened inhibitor.
2011-09-01 | GSE30530 | GEO
Project description:MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggests that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.
2018-06-06 | GSE107405 | GEO
Project description:ARF suppression by MYC but not MYCN confers increased malignancy of Group 3 medulloblastoma
| PRJNA578864 | ENA
Project description:Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis. APC-mutant intestinal stem cells (ISCs) outcompete their wild type neighbours through the secretion of Wnt antagonists, accelerating the fixation and subsequent rapid clonal expansion of mutants. Reports of polyclonal intestinal tumours in patients and mouse models appear at odds with this process. Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway level changes are accompanied by profound cancer stem cell phenotypic differences. Importantly, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways dependent on the differential activation of oncogenic pathways between clones.
2024-08-30 | GSE272850 | GEO
Project description:High-risk neuroblastoma (NB) often involves amplification of the neural MYC (MYCN) oncogene as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes such as MYCN and ALK result in increased replication stress in cancer cells, offering one such therapeutically exploitable option. Here, we followed up on earlier phosphoproteomic analyses that identified ATR activity in ALK-driven NB cell lines. We tested several ATR inhibitors, identifying BAY 1895344 as the most potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterized the response of NB cells and tumours to ATR inhibition, identifying key components of the DNA damage response (DDR) as well as ATRX, MYCN, E2F and DCK among other ATR targets in NB cells. ATR inhibition with BAY 1895344 also produced robust responses in mouse NB models. Remarkably, a 2 week protocol combining ATR and ALK inhibition led to complete regression of NB tumours in two independent NB genetically modified mouse tumour models. These results suggest that NB patients, particularly in high-risk groups with oncogene induced replication stress, may benefit from inhibition of ATR as therapeutic intervention.
2021-11-02 | PXD027187 | Pride
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.
2016-01-21 | E-GEOD-64425 | biostudies-arrayexpress
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 tumor’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.
2016-01-21 | GSE64425 | GEO
Project description:ARF is a tumour suppressor activated by oncogenic stress, which stabilizes p53. Although p53 is a key component of the response to DNA damage, a similar function for ARF has not been ascribed. In this work we show that homologous recombination (HR) -deficient primary mouse and human cells accumulate DNA damage, which triggers checkpoint signalling and ARF activation. We also show that in the absence of ARF p53 is induce in response to DNA damage, but surprisingly fails to trigger senescence. The hypothesis tested in this study was that ARF deficiency alters the spectrum of genes activated by p53 in response to HR deficiency. Using mRNA microarray analysis and expression profiling, we identified genes upregulated in wild type primary MEFs treated with RAD51 shRNA, whose expression was not induced in similarly treated Arf -/- primary MEFs. Clustering analysis of p53 transcriptional targets with increased expression in RAD51-depleted cells revealed three groups: genes requiring functional ARF for their expression, genes transcribed in an ARF-independent manner and genes that are upregulated in both ARF-proficient and ARF-deficient cells. Among the genes in the last group we found Cdkn1a(p21), encoding the p21 inhibitor of cyclindependent kinases and well-characterized effector of the p53 role in promoting senescence. The subset of p53 targets requiring ARF for their transcription was specifically upregulated in response to RAD51 inhibition in wild type, but not Arf -/- MEFs. Among these genes, two encoded the dual specificity phosphatase (DUSP) family members DUSP4 and DUSP7, which act as ERK phosphatases and negative regulators of the MAPK kinase pathway in mammalian cells.
2014-12-04 | GSE51354 | GEO
Project description:The aim of the study was to investigate gene expression tumour progression of KRas*/MYC driven lung tumours from adenocarcinoma in situ to invasive disease.
2018-06-01 | E-MTAB-6432 | biostudies-arrayexpress
Project description:ARF is a tumour suppressor activated by oncogenic stress, which stabilizes p53. Although p53 is a key component of the response to DNA damage, a similar function for ARF has not been ascribed. In this work we show that homologous recombination (HR) -deficient primary mouse and human cells accumulate DNA damage, which triggers checkpoint signalling and ARF activation. We also show that in the absence of ARF p53 is induce in response to DNA damage, but surprisingly fails to trigger senescence. The hypothesis tested in this study was that ARF deficiency alters the spectrum of genes activated by p53 in response to HR deficiency. Using mRNA microarray analysis and expression profiling, we identified genes upregulated in wild type primary MEFs treated with RAD51 shRNA, whose expression was not induced in similarly treated Arf -/- primary MEFs. Clustering analysis of p53 transcriptional targets with increased expression in RAD51-depleted cells revealed three groups: genes requiring functional ARF for their expression, genes transcribed in an ARF-independent manner and genes that are upregulated in both ARF-proficient and ARF-deficient cells. Among the genes in the last group we found Cdkn1a(p21), encoding the p21 inhibitor of cyclindependent kinases and well-characterized effector of the p53 role in promoting senescence. The subset of p53 targets requiring ARF for their transcription was specifically upregulated in response to RAD51 inhibition in wild type, but not Arf -/- MEFs. Among these genes, two encoded the dual specificity phosphatase (DUSP) family members DUSP4 and DUSP7, which act as ERK phosphatases and negative regulators of the MAPK kinase pathway in mammalian cells. Four samples were analysed (WT or ARF negative cells transfected with GFP or RAD51 shRNAs) in duplicate. Samples treated with GFP shRNA are the reference samples and the ones treated with RAD51 shRNA are the experimental ones (RAD51 depletion leads to HR deficiency). The WT cell line is our control cell line to study the effect of HR deficiency on the transcription of p53 target genes
2014-12-04 | E-GEOD-51354 | biostudies-arrayexpress