Large 1p36 deletions affecting Arid1a locus facilitate Mycn-driven oncogenesis in a new neuroblastoma model
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PROVIDER: PRJNA507631 | ENA |
REPOSITORIES: ENA
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Project description:Large 1p36 deletions affecting Arid1a locus facilitate Mycn-driven oncogenesis in a new neuroblastoma model
| PRJNA508091 | ENA
Project description:Loss of heterozygosity (LOH) at 1p36 is a frequent chromosomal event in a broad range of human cancers with increased incidence observed in nervous system malignancies, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions are highly correlated markers of tumor aggressiveness in NBL. While short distal 1p36 losses are associated with single copy MYCN tumors, larger hemizygous 1p deletions correlate with MYCN amplification, suggesting that two tumor suppressor regions exist in 1p36, a distal and proximal region, which have MYCN-independent and dependent roles. To interrogate this, we genome-edited a proximal candidate, Arid1a, a distal candidate, Chd5, and engineered a syntenic 1p36 LOH deletion in primary mouse NCCs, the likely cell of origin for NBL. Chd5 deletions were found to confer most of the pro-tumorigenic functions of 1p36 LOH in cells expressing endogenous Mycn levels. In contrast, reduced tumor latency in Mycn-driven oncogenesis significantly correlated with the loss of Arid1a. Gene expression analysis found that tumors presenting early onset display a Polycomb Repressive Complex 2 (PRC2) signature and an impaired Trp53 signaling pathway signature. Our findings delineate the tumor suppressor functions of 1p36 LOH in NBL and potentially provide critical insights for the constellation of cancers with 1p36 deletion.
2019-11-28 | GSE123142 | GEO
Project description:Loss of heterozygosity (LOH) at 1p36 is a frequent chromosomal event in a broad range of human cancers with increased incidence observed in nervous system malignancies, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions are highly correlated markers of tumor aggressiveness in NBL. While short distal 1p36 losses are associated with single copy MYCN tumors, larger hemizygous 1p deletions correlate with MYCN amplification, suggesting that two tumor suppressor regions exist in 1p36, a distal and proximal region, which have MYCN-independent and dependent roles. To interrogate this, we genome-edited a proximal candidate, Arid1a, a distal candidate, Chd5, and engineered a syntenic 1p36 LOH deletion in primary mouse NCCs, the likely cell of origin for NBL. Chd5 deletions were found to confer most of the pro-tumorigenic functions of 1p36 LOH in cells expressing endogenous Mycn levels. In contrast, reduced tumor latency in Mycn-driven oncogenesis significantly correlated with the loss of Arid1a. Gene expression analysis found that tumors presenting early onset display a Polycomb Repressive Complex 2 (PRC2) signature and an impaired Trp53 signaling pathway signature. Our findings delineate the tumor suppressor functions of 1p36 LOH in NBL and potentially provide critical insights for the constellation of cancers with 1p36 deletion.
2019-12-01 | GSE123281 | GEO
Project description:Loss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy MYCN tumors, larger deletions correlate with MYCN amplification, indicating two tumor suppressor regions in 1p36, only one of which facilitates MYCN oncogenesis. To better define this region, we genome-edited the syntenic 1p36 locus in primary mouse neural crest cells (NCCs), a putative NBL cell of origin. In in vitro cell transformation assays, we show that Chd5 loss confers most of the MYCN-independent tumor suppressor effects of 1p36 LOH. In contrast, MYCN-driven tumorigenesis selects for NCCs with Arid1a deletions from a pool of NCCs with randomly sized 1p36 deletions, establishing Arid1a as the MYCN-associated tumor suppressor. Our findings reveal that Arid1a loss collaborates with oncogenic MYCN and better define the tumor suppressor functions of 1p36 LOH in NBL.
| S-EPMC9022217 | biostudies-literature
Project description:Here we sought metabolic alterations specifically associated with amplified MYCN as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these were phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NMRI-Foxn1nu/nu mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHDGH knockout and inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach must be considered with caution in patients with neuroblastoma.
2020-12-11 | PXD018300 | Pride
Project description:Wilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. The proto-oncogene MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools. We screened a large cohort of unselected WTs and revealed frequencies of 3 % for MYCN P44L and 0.8 % for MAX R60Q, associated with a higher risk of relapse in the case of MYCN. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, and several of these are known for their oncogenic potential. Correlated expression in WT samples suggests a role in WT oncogenesis and they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.
2022-02-17 | PXD025996 | Pride
Project description:To evaluate the expression of genes associated with MYCN in NB, 10 tumors with MYCN amplification and 10 with normal MYCN copy number were subjected to oligonucleotide microarray using Agilent oligo microarray chips. Two-condition experiment, MYCN normal vs. MYCN amplified 10 NB patient tissues for each group.
2013-12-17 | E-GEOD-53371 | biostudies-arrayexpress
Project description:The RET gene has been identified previously as a target of activated ALK at the mRNA level in both human neuroblastoma cell lines and primary tumors as well as in murine tumors driven by mutated Alk and MYCN. Moreover, it has been shown that tumor growth of murine TH-MYCN/KI Alkmut tumors was impaired upon Ret inhibition by the vandetanib inhibitor, suggesting RET as a therapeutic target in ALK mutated neuroblastoma. To further demonstrate the crucial role of RET in ALK mutated driven neuroblastoma oncogenesis, transgenic TH-MYCN mice were bred with KI RetM919T tumors. We document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We used microarrays to analyze the global programme of gene expression of MYCN/RetM919T tumors and compare these profiles with profiles of MYCN/Alkmut tumors (GSE46583). Altogether, our data show that MYCN/RetM919T tumors present with expression profiles close to MYCN/Alkmut tumors.
2017-09-15 | GSE72678 | GEO
Project description:MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN in MNA+ NB, among which we uncover Myosin 1B (MYO1B) as being highly expressed in MNA+ NB. MYO1B promotes aggressive features, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling further delineate MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we find that MYO1B is upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB.
2023-10-24 | PXD039410 | Pride
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