High expression of MEIS1 without amplification was also found in other neuroblastoma cell lines, with and without MYCN amplification, and in medulloblastoma and crythroleukaemia cell lines.
In this fluorescence in situ hybridization study, we investigated the frequency and prognostic significance of MYCC and MYCN amplification in 77 medulloblastomas derived from the Children's Oncology Group.
Identical analyses were performed in a panel of medulloblastoma cell lines to identify c-Myc targets and to determine the extent to which N-Myc targets and c-Myc targets were shared.
Loss of 17p13.3 (38% of medulloblastomas) was found across all of the histopathological variants, whereas MYCC/MYCN amplification (6%/8% of medulloblastomas) was significantly associated with the large cell/anaplastic phenotype.
More detailed FISH analysis showed that coamplification of MYCN and TERT in one of the MBs manifested as dispersed nuclear speckling, consistent with the presence of double minute chromosomes.
MYCN-driven MB showed either classic or LCA pathologies, with Shh signaling activated in approximately 5% of tumors, demonstrating that MYCN can drive MB independently of Shh.
TP53 mutation status was not associated with unfavorable prognosis (P = .63) and was not linked to 17p allelic loss but was over-represented in the prognostically favorable WNT subgroup of MB as defined by CTNNB1 mutation (seven of 35 TP53-mutated tumors v 14 of 271 TP53 wild-type tumors; P = .005) and in tumors carrying high-level MYCN amplification (seven of 21 TP53-mutated tumors v 14 of 282 TP53 wild-type tumors; P = .001).
MYCN is a transcription factor that is expressed during the development of the neural crest and its dysregulation plays a major role in the pathogenesis of pediatric cancers such as neuroblastoma, medulloblastoma and rhabdomyosarcoma.
Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults.
We found that Sna1 directly induced transcription of N-Myc in human medulloblastoma cells and that depletion of N-Myc ablated the Sna1-induced proliferation and transformation.
We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB).
This mouse model should significantly accelerate understanding and treatment of the most aggressive form of medulloblastoma and infers distinct roles for MYC and MYCN in tumorigenesis.
This finding also confirms the importance of impairment of the MYC/MAX/MXD1 axis in the development of aggressive neural tumors, because MYCN overexpression is an established genetic hallmark of malign neuroblastoma, and it is likely that MXI1 plays a relevant role in the development of medulloblastoma and glioblastoma.
Using AGDEX analysis and k-means clustering, we show that the Blbp-cre::Ctnnb1(ex3)(Fl/+)Trp53 (Fl/Fl) mouse model fits well to human WNT medulloblastoma, and that, among various Myc- or Mycn-based mouse medulloblastomas, tumors in Glt1-tTA::TRE-MYCN/Luc mice proved to be most specific for human group 3 medulloblastoma.
To better understand the role of MYCN in MB in vitro and in vivo and to aid the development of MYCN-targeted therapeutics we established tumor-derived neurosphere cell lines from the GTML (Glt1-tTA/TRE-MYCN-Luc) genetically engineered mouse model.
To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations.