Genetic Alterations in Mouse Medulloblastomas and Generation of Tumors<i>De novo</i>from Primary Cerebellar Granule Neuron Precursors

Zindy, Frédérique; Uziel, Tamar; Ayrault, Olivier; Calabrese, Christopher; Valentine, Marc; Rehg, Jerold E.; Gilbertson, Richard J.; Sherr, Charles J.; Roussel, Martine F.

doi:10.1158/0008-5472.can-06-3418

Cited by 70 publications

(105 citation statements)

References 28 publications

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“…Purification of GNPs from mouse cerebella and MBs were done as described (22). Infection of GNPs and orthotopic injections were carried out as described using 2 ϫ 10 6 cells (27). To assess the infection efficiency, 3 ϫ 10 5 infected cells were cultured for 48 h, then fixed and immunostained with anti-GFP.…”

Section: Methodsmentioning

confidence: 99%

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The miR-17 ∼ 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma

Uziel¹,

Karginov

Xie³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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274

221

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Medulloblastomas (MBs) are the most common brain tumors in children. Some are thought to originate from cerebellar granule neuron progenitors (GNPs) that fail to undergo normal cell cycle exit and differentiation. Because microRNAs regulate numerous aspects of cellular physiology and development, we reasoned that alterations in miRNA expression might contribute to MB. We tested this hypothesis using 2 spontaneous mouse MB models with specific initiating mutations, Ink4c؊/؊; Ptch1؉/؊ and Ink4c؊/؊; p53؊/؊. We found that 26 miRNAs showed increased expression and 24 miRNAs showed decreased expression in proliferating mouse GNPs and MBs relative to mature mouse cerebellum, regardless of genotype. Among the 26 overexpressed miRNAs, 9 were encoded by the miR-17ϳ92 cluster family, a group of microRNAs implicated as oncogenes in several tumor types. Analysis of human MBs demonstrated that 3 miR-17ϳ92 cluster miRNAs (miR-92, miR-19a, and miR-20) were also overexpressed in human MBs with a constitutively activated Sonic Hedgehog (SHH) signaling pathway, but not in other forms of the disease. To test whether the miR-17ϳ92 cluster could promote MB formation, we enforced expression of these miRNAs in GNPs isolated from cerebella of postnatal (P) day P6 Ink4c؊/؊; Ptch1؉/؊ mice. These, but not similarly engineered cells from Ink4c؊/؊; p53؊/؊ mice, formed MBs in orthotopic transplants with complete penetrance. Interestingly, orthotopic mouse tumors ectopically expressing miR-17ϳ92 lost expression of the wild-type Ptch1 allele. Our findings suggest a functional collaboration between the miR-17ϳ92 cluster and the SHH signaling pathway in the development of MBs in mouse and man.cerebellum ͉ microRNAs ͉ oncomiR1 ͉ granule neuron progenitors

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Section: Methodsmentioning

confidence: 99%

“…wc, whole cerebellum; WT, wild type. culture (27). All (9/9 injections) populations of Ink4cϪ/Ϫ; Ptch1ϩ/Ϫ GNPs, but none (0/4 injections) from Ink4cϪ/Ϫ; p53Ϫ/Ϫ mice transduced with human hsa-miR-17ϳ92 cluster formed tumors, with a latency of 1.5 to 5 months ( Table 1).…”

Section: The Human Mb Subgroup With An Activated Shh/patched Signalingmentioning

confidence: 99%

The miR-17 ∼ 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma

Uziel¹,

Karginov

Xie³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

274

221

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“…It is not, therefore, surprising that MYC expression is elevated in tumors driven by constitutive WNT signaling. Furthermore, many mouse models of medulloblastoma have been developed through enforced MYC and MYCN expression in various cell types throughout the posterior fossa and none of these results in the formation of WNT subgroup (Zindy et al 2007;Swartling et al 2010;Kawauchi et al 2012;Swartling et al 2012). These data suggest that MYC's relationship to the WNT subgroup is not tumorigenic or progressive, but rather a marker of enhanced WNT pathway activity.…”

Section: Myc In the Wnt Subgroupmentioning

confidence: 99%

“…Robinson Northcott et al 2012a;Pugh et al 2012;Robinson et al 2012). Numerous mouse models of this disease have been developed by engineering mutations that activate the SHH pathway (Goodrich et al 1997;Hallahan et al 2004;Uziel et al 2005;Zindy et al 2007;Hatton et al 2008;Ayrault et al 2010).…”

Section: Myc In the Shh Subgroupmentioning

confidence: 99%

“…Activation of the SHH pathway promotes the expression and stabilization of MYCN (Oliver et al 2003;Thomas et al 2009). Enforced expression of MYCN in granule neural precursors (GNPs) collaborates with the loss of one copy of the Ptch1 mutant and Cdkn2c ( p18 Ink4c ), or with the loss of Trp53 and Cdkn2c to accelerate SHH MB development in mice from 9 to 3 months after birth and to increase penetrance from 14% to 60% (Uziel et al 2005;Zindy et al 2007;Ayrault et al 2009;Kawauchi et al 2012). Moreover, enforced MYCN expression produces more invasive, drug-resistant tumors (Kessler et al 2009).…”

Section: Myc In the Shh Subgroupmentioning

confidence: 99%

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Role of MYC in Medulloblastoma

Roussel

Robinson

2013

Cold Spring Harbor Perspectives in Medicine

134

109

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Since its discovery as an oncogene carried by the avian acute leukemia virus MC29 in myelocytomatosis (Roussel et al. 1979) and its cloning (Vennstrom et al. 1982), c-MYC (MYC), as well as its paralogs MYCN and MYCL1, has been shown to play essential roles in cycling progenitor cells born from proliferating zones during embryonic development, and in all proliferating cells after birth. MYC deletion induces cell-cycle exit or cell death, depending on the cell type and milieu, whereas MYC and MYCN amplification or overexpression promotes cell proliferation and occurs in many cancers. Here, we review the relationship of MYC family proteins to the four molecularly distinct medulloblastoma subgroups, discuss the possible roles MYC plays in each of these subgroups and in the developing cells of the posterior fossa, and speculate on possible therapeutic strategies targeting MYC.

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Insights into Wild-Type and Mutant p53 Functions Provided by Genetically Engineered Mice

Donehower

2014

Human Mutation

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Genetic Alterations in Mouse Medulloblastomas and Generation of TumorsDe novofrom Primary Cerebellar Granule Neuron Precursors

Cited by 70 publications

References 28 publications

The miR-17 ∼ 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma

The miR-17 ∼ 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma

Role of MYC in Medulloblastoma

Insights into Wild-Type and Mutant p53 Functions Provided by Genetically Engineered Mice

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