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Review
. 2013 Oct 1;3(10):a014415.
doi: 10.1101/cshperspect.a014415.

Neuroblastoma and MYCN

Miller Huang  1 , William A Weiss
Affiliations
Review

Neuroblastoma and MYCN

Miller Huang et al. Cold Spring Harb Perspect Med. .

Abstract

Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to originate from undifferentiated neural crest cells. Amplification of the MYC family member, MYCN, is found in ∼25% of cases and correlates with high-risk disease and poor prognosis. Currently, amplification of MYCN remains the best-characterized genetic marker of risk in neuroblastoma. This article reviews roles for MYCN in neuroblastoma and highlights recent identification of other driver mutations. Strategies to target MYCN at the level of protein stability and transcription are also reviewed.

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Figures

Figure 1.
Figure 1.
Similarities and differences between MYC and MYCN. MYC and MYCN are similar both in (A) structure (homologous sequences in red), and (B) biological functions. However, MYC and MYCN differ in (C) the spatiotemporal expression levels. In particular, MYCN is preferentially expressed in neural tissue, whereas MYC is more ubiquitously expressed. Expression of MYC and MYCN at each tissue is based on a relative percentage of the highest expressing tissue (newborn forebrain for MYCN and newborn thymus for MYC), which was arbitrarily set to 100%. (Panel A based on Hartl et al. 2010. Panel C based on data from Zimmerman et al. 1986.)
Figure 2.
Figure 2.
MYCN plays multiple roles in malignancy and maintenance of stem-like state. MYCN can activate transcription of genes involved in metastasis, survival, proliferation, pluripotency, self-renewal, and angiogenesis. Additionally, MYCN can suppress expression of genes that promote differentiation, cell cycle arrest, immune surveillance, and genes that antagonize metastasis and angiogenesis. Because MYCN also activates apoptotic pathways involving p53, MYCN is not normally sufficient for transformation.
Figure 3.
Figure 3.
Amplified MYCN marks chemoresistance in patients with neuroblastoma. (A,B) Amplified MYCN results in elevated transcription of MDM2 and TP53. High levels of p53 sensitize tumors to apoptosis. (C) Patients initially respond to chemotherapy as p53 triggers apoptosis. (D) At relapse, tumors show mutation in p53 or p53 pathways, resulting in therapy resistance.
Figure 4.
Figure 4.
Therapeutic strategies to target MYCN in neuroblastoma. Possible strategies to treat MYCN-amplified neuroblastoma patients include (A) blocking MYCN-dependent transcription with BET-bromodomain inhibitors, (B) inhibiting HDACs, (C) antagonizing proteins involved in stabilizing MYCN protein, (D) suppressing MDM2 (which stabilizes MYCN mRNA and disrupts p53-mediated apoptosis), and (E) inducing differentiation.
See this image and copyright information in PMC

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