Lack of Rb and p53 Delays Cerebellar Development and Predisposes to Large Cell Anaplastic Medulloblastoma through Amplification of N-Myc and Ptch2

Abstract

Medulloblastomas are among the most common malignant brain tumors in childhood. They typically arise from neoplastic transformation of granule cell precursors in the cerebellum via deregulation of molecular pathways involved in normal cerebellar development. In a mouse model, we show here that impairment of the balance between proliferation and differentiation of granule cell precursors in the external granular layer of the developing cerebellum predisposes but is not sufficient to induce neoplastic transformation of these progenitor cells. Using array-based chromosomal comparative genomic hybridization, we show that genetic instability resulting from inactivation of the p53 pathway together with deregulation of proliferation induced by Rb loss eventually leads to neoplastic transformation of these cells by acquiring additional genetic mutations, mainly affecting N-Myc and Ptch2 genes. Moreover, we show that p53 loss influences molecular mechanisms that cannot be mimicked by the loss of either p19 ARF , p21, or ATM.

Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas

“…Similarly no expression of GABARa6 and only very weak expression of Gli1 was detected in all three cNSC medulloblastomas as compared to the strong expression of both genes in the adult cerebellum and in 2 out of 3 EGL medulloblastomas (Figure 3c). Interestingly, expression of ptch2 and N-Myc, which we found significantly upregulated in EGL medulloblastoma (Shakhova et al, 2006), was significantly lower in cNSC medulloblastoma (Supplementary Figure S3), therefore implying that a different molecular mechanism might be involved in the pathogenesis of these tumors.…”

“…After a latency of 20 weeks medulloblastomas occur in the cerebellum with 100% penetrance. These tumors show remarkable similarities to the large cell anaplastic variant of human medulloblastoma, including similar histology, highly aggressive behavior (Marino et al, 2000) and acquisition of additional genetic mutations mainly affecting N-Myc (Shakhova et al, 2006). Here we have taken advantage of this powerful experimental system in which medulloblastomas arise with full penetrance when permissive cells are targeted to address the question of whether postnatal cNSCs can function as medulloblastoma-initiating cells and whether different ontogenetic mechanisms can have a role in explaining the heterogeneity of these tumors in humans.…”

N-myc alters the fate of preneoplastic cells in a mouse model of medulloblastoma

“…The ability of N-myc to increase the incidence of medulloblastoma is consistent with several previous reports. Cold Spring Harbor Laboratory Press on May 11, 2018 -Published by genesdev.cshlp.org Downloaded from 2002) and in several mouse models of the disease (Shakhova et al 2006;Yan et al 2006;Frappart et al 2007;Zindy et al 2007), often in conjunction with mutation or deletion of ptc. Moreover, N-myc retroviruses cooperate with Shh retroviruses to transform GNPs in the neonatal cerebellum (Browd et al 2006), and overexpression of Nmyc in GNPs that lack p53 and Ink4c allows these cells to give rise to tumors in a transplantation assay (Zindy et al 2007).…”

“…To test whether nontumorigenic PNCs can be induced to form tumors, we sought to provide them with a ''second hit.'' We chose the N-myc oncogene because it has been shown to be amplified or overexpressed in human medulloblastoma (Aldosari et al 2002;Eberhart et al 2002;Pomeroy et al 2002) as well as in several mouse models of the disease (Shakhova et al 2006;Yan et al 2006;Frappart et al 2007;Zindy et al 2007). We isolated PNCs from individual ptc +/À mice, infected half the cells with a control GFP retrovirus and half with an N-myc-IRES-GFP retrovirus, and then implanted cells into the cerebellum of SCID-beige hosts.…”

Medulloblastomas Derived from Cxcr6 Mutant Mice Respond to Treatment with a Smoothened Inhibitor

“…Indeed, the deletion of chromosome 3p21.3, which contains a large cluster of chemokine receptors including the CXCR6 gene (35), has been observed in several human cancers (43,44 (20). Although genetic instability resulting from inactivation of the p53 pathway contributes to neoplastic transformation of granule cell precursors (5,41), the precise molecular mechanism is unclear. It is possible that loss of Cxcr6 also promotes medulloblastoma formation in a similar manner to loss of p53 and, therefore, tumorigenesis is not further accelerated by loss of p53.…”