MYC-family protein overexpression and prominent nucleolar formation represent prognostic indicators and potential therapeutic targets for aggressive high-MKI neuroblastomas: A report from the children's oncology group

Risa Niemas-Teshiba, Ryosuke Matsuno, Larry L. Wang, Xao X. Tang, Bill Chiu, Jasmine Zeki, Jeannine Coburn, Kimberly Ornell, Arlene Naranjo, Collin Van Ryn, Wendy B. London, Michael D. Hogarty, Julie M. Gastier-Foster, A. Thomas Look, Julie R. Park, John M. Maris, Susan L. Cohn, Robert C. Seeger, Shahab Asgharzadeh, Naohiko IkegakiHiroyuki Shimada

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with MYCN amplification, MYCN protein overexpression and adverse clinical outcome. However, the prognostic effect of MYC-family protein expression on these neuroblastomas is less understood, especially when MYCN is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120 MYCN amplified and 121 non-MYCN amplified) was examined by immunohistochemistry. The majority (101) of MYCN-amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non-MYCN-amplified cases appeared heterogeneous, including 7 MYCN(+), 36 MYC(+), 3 both(+), and 75 both(-)/(+/-) tumors. These MYC-family proteins(+), or MYC-family driven tumors, were most likely to have prominent nucleolar (PN) formation (indicative of augmented rRNA synthesis). High-MKI neuroblastoma patients showed a poor survival irrespective of MYCN amplification. However, patients with MYC-family driven High-MKI neuroblastomas had significantly lower survival than those with non-MYC-family driven tumors. MYCN(+), MYC-family protein(+), PN(+), and clinical stage independently predicted poor survival. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and neuroblastoma growth. Together, MYC-family protein overexpression and PN formation should be included in new neuroblastoma risk stratification and considered for potential therapeutic targets.

Original languageEnglish (US)
Pages (from-to)6416-6432
Number of pages17
JournalOncotarget
Volume9
Issue number5
DOIs
StatePublished - 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was in part supported by NIH grants; U10CA180899, U10CA98543, PO1CA081403, NS094218, and R01CA127571.

Publisher Copyright:
© Niemas-Teshiba et al.

Keywords

  • Aminoacyl-tRNA synthetase
  • CX-5461
  • Halofuginone
  • Nucleolar hypertrophy
  • Protein translation

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