We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice).
G<sub>D2</sub> concentrations were significantly higher in serum from children with MYCN-amplified tumors (P = 0.0088), high-risk tumors (P < 0.00001), International Neuroblastoma Staging System (INSS) stage 4 tumors (P < 0.00001), and in children who died (P = 0.034).
Combined targeting of HBP1 by PI<sub>3</sub>K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.
Tumors expressing NTRK1-pY674/pY675 and low or undetectable levels of PTPN6 and TP53 were significantly associated with 5-year RFS (P = .014) when the dataset was stratified by MYCN amplification, segmental chromosomal abnormalities and histology.
N-Myc downstream-regulated gene 2 (NDRG2) was characterized as a tumor suppressor, inducing anti-metastatic and anti-proliferative effects in several tumor cells.
Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination.
High expression of MYCN RNA was significantly associated with MYCN amplification (P < 0.001) and other adversely prognostic factors, including older age at diagnosis (>18 months, P = 0.017), advanced clinical stage (International Neuroblastoma Staging System stage 3, 4, P = 0.002), unfavorable International Neuroblastoma Pathology Classification tumor histology (P < 0.001), and high-risk Children's Oncology Group risk group (P = 0.001).
Because BRCA1 is highly expressed in neuronal progenitor cells during early development<sup>4</sup> and MYC is less efficient than MYCN in recruiting BRCA1, our findings indicate that a cell-lineage-specific stress response enables MYCN-driven tumours to cope with deregulated RNAPII function.
Whilst N-Myc amplification status strongly correlates with higher tumour aggression and resistance to treatment, the role of N-Myc in the aggressiveness of the disease is poorly understood.
The present results suggest that MYCN may be a promising biomarker for HB and a potential therapeutic target in patients with tumors overexpressing MYCN.
We also administered interferon beta-transduced mMSCs (mMSCs-IFN-β) to MYCN-TgM i.p. and measured the concentration of IFN-β in the tumor and organs by an enzyme-linked immunosorbent assay (ELISA).
We also discuss the subtype of retinoblastoma driven by the MYCN oncogene more commonly associated with neuroblastoma, and consider trilateral retinoblastoma, in which an intracranial tumor arises along with ocular tumors in patients with germline RB1 gene mutations.
NXS2 had a moderate tumor mutation burden (TMB) while N-MYC driven 9464D-GD2 had a low TMB, therefore the latter served as a better model for high-risk neuroblastoma (an immunologically cold tumor).
In this study, we show that natural killer (NK) cell-derived exosomes carrying the tumor suppressor microRNA (miR)-186 exhibit cytotoxicity against MYCN-amplified neuroblastoma cell lines.
Interestingly, western blot and metabolite analysis showed that the tumor suppressor NDRG2 (N-Myc downstream regulated gene 2) was able to inhibit mTORC1 activity and cooperate with an mTOR inhibitor to decrease aerobic glycolysis in 786-O and ACHN cells.
The result showed that it negatively correlated to relapse-free survival probability significantly in patients with neuroblastoma with non-MYCN amplified tumor.
Amplified copies of MYCN are considered the most important marker for the prediction of tumour relapse and progression in NB, but they were only detected in 20-30% of NB patients, indicating there might be other oncogenes in the development of NB.
The subset of patients with 4S disease with MYCN-not amplified tumors with impaired or impending organ dysfunction, or with unfavorable histology and/or diploid DNA index, were eligible.