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

• Published in: Oncotarget Vol. 9; no. 5; pp. 6416 - 6432
• Main Authors: Niemas-Teshiba, Risa, Matsuno, Ryosuke, Wang, Larry L, Tang, Xao X, Chiu, Bill, Zeki, Jasmine, Coburn, Jeannine, Ornell, Kimberly, Naranjo, Arlene, Van Ryn, Collin, London, Wendy B, Hogarty, Michael D, Gastier-Foster, Julie M, Look, A Thomas, Park, Julie R, Maris, John M, Cohn, Susan L, Seeger, Robert C, Asgharzadeh, Shahab, Ikegaki, Naohiko, Shimada, Hiroyuki
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 19.01.2018
• Subjects: Research Paper; protein translation; nucleolar hypertrophy; CX-5461; aminoacyl-tRNA synthetase; halofuginone
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.23740

Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with 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 is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120 amplified and 121 non- amplified) was examined by immunohistochemistry. The majority (101) of -amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non- -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 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.