Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC

University of California, Department of Neurology, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Cancer cell (Impact Factor: 23.52). 05/2012; 21(5):601-13. DOI: 10.1016/j.ccr.2012.04.012
Source: PubMed


The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-myc(T58A) into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-myc(WT) NSCs was insufficient for tumor formation. N-myc(T58A) cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.

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    • "The G34V mutation was linked to an altered transcriptional status of the cells, with quite widespread changes in RNA polymerase II association and levels of K36 methylation when compared with a glioma cell line wild-type for H3.3. One locus that was particularly induced was MYCN, an oncogene implicated in pediatric glioblastoma (Swartling et al. 2012). Transduction of G34V mutant H3.3 into normal human astrocytes or into transformed human fetal glial cells was sufficient to induce N- MYC expression two-to threefold over cells transduced with WT H3.3 (Bjerke et al. 2013). "
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