Myc proteins in brain tumor development and maintenance 123 proteins can use different strategies in their role as master regulators of cell proliferation and in tumor maintenance. Medulloblastoma biology Brain tumors represent the most common solid tumor of childhood. The embryonal tumor medul- loblastoma (MB) is next to leukemia the most common malignancy in children (25). Treatment includes surgery, radiation, and chemotherapy, which cures about 70% (26), although survivors can have severe long-term side-effects following this treatment. MB can be categorized into different subtypes (27) presenting a desmoplastic or nodular, classic, and large cell/anaplastic (LCA) pathology, where the LCA subtype shows monomorphic cells with large nuclei and correlates with the poorest outcome. Advanced genomic and transcriptional proﬁling has recently offered reliable molecular classiﬁcation of human MB (28–31). This provides a better classiﬁcation of these childhood tumors, which will facilitate better strategies for improved patient treatment. Abnormal activation of molecular pathways like Sonic Hedgehog (SHH) and Wingless (WNT) signaling contributes to tumorigenesis in some patients; however, the majority show no abnor- malities in these pathways and are referred to as Group 3 or Group 4 MB (32). Wnt signaling abnor- malities involving beta-catenin nuclear staining occur in 10%–15% of patients and have been described as a marker for favorable outcome (33,34). Such tumors have recently been found to originate from BLBP-positive cells of the lower rhombic lip structure in the developing dorsal brain stem (35). Another developmental pathway believed to have a critical role in MB maintenance is Notch. Inhibiting Notch suppresses MB in vivo by apoptosis and may prove effective in MB therapy (36,37), even if Notch is not required in Shh-dependent MB subtypes (38,39). Shh-dependent MB only repre- sents about 25% of MB cases. Nevertheless there are numerous reports of Shh-dependent models that recapitulate human Shh-dependent MB in mice (see recent review (40)); the ﬁrst were models that activated the pathway through loss of Patched (41). Ampliﬁcation of MYC or MYCN occurs in about 10% of human MB and correlates with a 5-year overall survival of only 13% (11). Both MYC and MYCN ampliﬁcations further associate with an aggressive LCA medulloblastoma pathology (10,42,43). MYCN is expressed at high levels in SHH-associated MB (10) and is actually essential for Shh-dependent tumors in mouse models of this disease (17). However, most Shh-independent human MB also express MYCN (20,44,45). Indeed, in a model where human MYCN drives MB formation from the glutamate transporter 1 (Glt1) promoter in cerebellar cells, the majority of the developed brain tumors are actually Shh-indepen- dent (20). This MB model thus correlates with recent ﬁndings (34,46) that suggest a majority of MYCN- ampliﬁed human MB are categorized as non-SHH Group 4 MB (46). Glioma biology Glioma, the most common primary brain tumors in adults, is classiﬁed as grade I to IV according to the World Health Organization (WHO) (47). Of high- grade gliomas (grade III and IV), glioblastoma (GBM) is the most common and most malignant (grade IV) tumor with dismal outcome. GBMs account for 60%–70% of malignant glioma (48). While grade III gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma) are characterized by increased cellularity, nuclear aty- pia, and proliferative activity, GBMs also contain areas of microvascular proliferation and necrosis. GBMs have a 5-year overall survival of less than 10% despite an increased survival effect from the use of the alkylat- ing agent temozolomide following tumor resection and radiation (49). An effort to stratify GBMs further and to enable a more individualized therapy is further to classify these malignant brain tumors into different subtypes characterized by molecular abnormalities (50–52). The most recent efforts of genomic proﬁling from The Cancer Genome Atlas (TCGA) Research Network have deﬁned four subgroups of GBM: pro- neural, neural, classical, and mesenchymal. These subgroups show signature aberrations where the gene expression of EGFR, NF1, and PDGFRA/ IDH1 can help deﬁne a classical, mesenchymal, and proneural subtype, respectively (52). There are many reports in which Myc proteins have been ampliﬁed or overexpressed in glioma (53–56). Interestingly, MYCN showed high-level focal ampliﬁcations in a subset of GBM samples (51), and MYC or MYCN is found to be ampliﬁed in almost half of brain cancers that have combined features of malignant glioma and primitive neuroectodermal tumors (MG-PNET) (15). Interestingly, p53, which is directly or indirectly inac- tivated in 87% of GBMs (TCGA), represses MYC transcription by directly binding to the MYC promoter (57). Most important, c-myc plays a critical role in the regulation and especially the proliferation of glioma stem cells, which are the putative cells of origin for these brain tumors (58-60). This suggests that Myc proteins are master regulators also for these types of brain tumors.