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Myc Proteins As Therapeutic Targets Oncogene (2010) 29, 1249–1259 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc REVIEW Myc proteins as therapeutic targets WC Gustafson1,2 and WA Weiss1,3,4 1Department of Pediatrics, University of California, San Francisco, CA, USA; 2Division of Pediatric Hematology/Oncology, University of California, San Francisco, CA, USA; 3Department of Neurology, University of California, San Francisco, CA, USA and 4Department of Neurosurgery, University of California, San Francisco, CA, USA Myc proteins (c-myc, Mycn and Mycl) target prolifera- tumors and is the best characterized genetic-risk factor tive and apoptotic pathways vital for progression in for high-risk chemotherapy-refractory disease (Brodeur cancer. Amplification of the MYCN gene has emerged et al., 1984; Seeger et al., 1985; Riley et al., 2004). as one of the clearest indicators of aggressive and Deletion or suppression of caspase 8, loss of chromo- chemotherapy-refractory disease in children with neuro- somes 1p and 11q, and gain of 17q also correlate with blastoma, the most common extracranial solid tumor of aggressive disease (Bown et al., 1999; Guo et al., 1999; childhood. Phosphorylation and ubiquitin-mediated mod- Riley et al., 2004; Attiyeh et al., 2005; Stupack et al., ulation of Myc protein influence stability and represent 2006; Maris et al., 2008b). potential targets for therapeutic intervention. Phosphor- In contrast with most other treatment-refractory ylation of Myc proteins is controlled in-part by the cancers, neuroblastomas, irrespective of risk group, receptor tyrosine kinase/phosphatidylinositol 3-kinase/ generally respond to initial therapy, which typically Akt/mTOR signaling, with additional contributions from includes high doses of chemotherapy (Park et al., 2008). Aurora A kinase. Myc proteins regulate apoptosis in part Low- and intermediate-risk patients are subsequently through interactions with the p53/Mdm2/Arf signaling cured and rarely progress. Patients with high-risk pathway. Mutation in p53 is commonly observed in disease typically relapse with treatment-refractory tu- patients with relapsed neuroblastoma, contributing to mors. It is conceivable that low- and high-risk neuro- both biology and therapeutic resistance. This review blastoma are entirely separate disease entities. Overall, examines Myc function and regulation in neuroblastoma, prognosis in the high-risk group is quite poor, with long- and discusses emerging therapies that target Mycn. term survival of 30–40%. Oncogene (2010) 29, 1249–1259; doi:10.1038/onc.2009.512; published online 25 January 2010 Familial neuroblastoma Keywords: myc; mycn; neuroblastoma; N-myc; mTor; PI3K Neuroblastoma may be associated with Hirschsprung disease and neurofibromatosis type 1 (Clausen et al., 1989; Rohrer et al., 2002). Mutations in PHOX2B,a homeodomain-containing transcription factor important Introduction for the development in the autonomic nervous system, underlie the congenital central hypoventilation syndrome Neuroblastoma, a neoplasm of peripheral neural crest and confer a heritable predisposition to neuroblastoma; origin, is the most common malignant extracranial solid however, these mutations are not found in spontaneous tumor of childhood and accounts for 15% of cancer tumors (Mosse et al.,2004;Trochetet al.,2005;Raabe deaths in children (Park et al., 2008). Approximately 650 et al., 2008). In fact, familial neuroblastoma is quite rare, new cases are diagnosed in the United States annually and is most often because of dominant gain-of-function with peak incidence in early childhood (ages 0–4 years). mutations in the orphan receptor tyrosine kinase (RTK) The most common site of origin is in the adrenal anaplastic lymphoma kinase (ALK). ALK, which is linked medulla; however, tumors can occur anywhere along the to MYCN on chromosome 2p23, also shows sporadic gain- sympathetic chain. of-function mutation in 8% of spontaneous tumors (Chen Patients with new diagnoses are typically stratified et al., 2008; George et al., 2008; Janoueix-Lerosey et al., into risk groups based on age, stage, histopathology, 2008; Mosse´et al., 2008). Although direct connections DNA index and genetic/genomic factors. Amplification between MYCN and ALK have yet to be elucidated, of the proto-oncogene MYCN occurs in B25% of activation of Alk and other RTKs may contribute to stabilization of Mycn protein (detailed below). Correspondence: Dr WC Gustafson, Pediatric Hematology/Oncology, University of California, Helen Diller Family Cancer Research Myc family of proto-oncogenes Building, 1450 3rd Street, San Francisco, CA 94158-9001, USA. E-mail: [email protected] Received 22 September 2009; revised 9 December 2009; accepted 15 Broadly implicated in oncogenesis, the human MYC December 2009; published online 25 January 2010 family of proto-oncogenes is among the most studied Mycn signaling in neuroblastoma WC Gustafson and WA Weiss 1250 genes in cancer (Meyer and Penn, 2008). Early inser- Chromatin immunoprecipitation experiments show tional mutagenesis studies in mouse identified c-MYC that c-Myc and Mycn proteins bind to promoters with (homologous to the v-myc gene that drives avian variable specificity determined by DNA ultrastructure myelocytosis) as capable of transformation by retroviral and cellular context (Fernandez et al., 2003; Li et al., promoter insertion (Payne et al., 1982). MYCN was 2003; Mao et al., 2003; Chen et al., 2004; Guccione subsequently identified as an MYC homolog amplified et al., 2006; Zeller et al., 2006; Kim et al., 2008; in neuroblastoma tumors (reviewed in Meyer and Penn, Martinato et al., 2008; Westermann et al., 2008). Myc/ 2008). Amplification of MYCN has emerged as among Max heterodimers bind to E-boxes and interact with a the clearest genetic indicators of high-risk, aggressive variety of histone modifiers, increasing histone acetyla- disease (Brodeur et al., 1984; Seeger et al., 1985). MYC tion (Bouchard et al., 2001). These alterations modify family members (c-MYC, MYC and MYCL) show chromatin at promoters, affecting gene expression differential expression in normal tissues. Expression of (McMahon et al., 2000; Frank et al., 2001; Vervoorts murine N-myc in particular is elevated in normal et al., 2003; Guccione et al., 2006; Martinato et al., 2008; mammalian developing retina, forebrain, hindbrain, Liu et al., 2009). In fact, histone modification by Mycn intestine, kidney and has functions in neuronal progeni- effectors is being exploited pharmacologically using tor cells, developing lung tissues, hematopoetic stem histone deacetylase inhibitors. These drugs may alter cells and programmed cell death in the developing limb acetylation in neuroblastomas and other MYC depen- (Zimmerman et al., 1986; Mugrauer et al., 1988; Downs dent processes thereby modulating transcription (re- et al., 1989; Hirvonen et al., 1990; Hirning et al., 1991; viewed in Witt et al., 2009). Knoepfler et al., 2002; Bettess et al., 2005; Okubo et al., Several studies have attempted to elucidate specific 2005; Ota et al., 2007; Martins et al., 2008; Xu et al., transcriptional targets for Mycn in neuroblastoma 2009). (Alaminos et al., 2003). A large number of targets Myc proteins are basic helix-loop-helix leucine zipper important for cell cycle control and differentiation have transcription factors. Mycn and c-Myc proteins share been characterized, including: downregulation of SKP2 several regions of homology and share similar cellular and TP53INP1 with resultant decrease in p21WAF1 (Bell functions. Myc proteins localize to the nucleus and form et al., 2007), downregulation of DKK1 upstream of the heterodimers with the basic helix-loop-helix molecule, wnt/b-catenin pathway (Koppen et al., 2007), upregula- Max (Blackwood and Eisenman, 1991; Prendergast tion of NLRR1 both important in neural cell prolifera- et al., 1991; Berberich and Cole, 1992; Blackwood tion (Hossain et al., 2008), downregulation of Fyn et al., 1992; Kato et al., 1992). Myc/Max heterodimers kinase important in differentiation (Berwanger et al., bind to DNA at specific CAC(G/A)TG ‘E-box’ se- 2002), regulation of multiple genes responsible for quences to drive transcription of targets important for pluripotency (Cotterman and Knoepfler, 2009) and proliferation, apoptosis and differentiation (Blackwell modulation of apoptosis by upregulation of p53 and et al., 1990, 1993; Amati et al., 1992; Kretzner et al., Mdm2 (Slack et al., 2005b). The multidrug resistance 1992). Max also heterodimerizes with Mxd or Mnt gene MRP1 is regulated by Mycn, driving chemotherapy proteins to influence the transcription of other down- resistance (Manohar et al., 2004). Importantly, Mycn stream genes and often to antagonize the proliferative upregulates oncogenic microRNAs, which have wide effects of Myc proteins (Ayer et al., 1993; Zervos et al., ranging effects on cancer (reviewed in Schulte et al., 1993; Hurlin et al., 1995, 1997; Walkley et al., 2005). In 2009). Mycn also controls several proteins important in many systems, Mxd/Max or Mnt/Max heterodimers ribosome biogenesis (Boon et al., 2001) affecting protein oppose the actions of Myc/Max to repress transcription; synthesis (reviewed in Ruggero, 2009). however, very little is known about these interactions in Different groups seeking to stratify neuroblastoma neuroblastoma (Grandori et al., 2000; Patel et al., 2004). risk using gene expression micoarrays have generated The complex competition among Myc, Mxd and Mnt gene lists that are largely non-overlapping (Berwanger
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