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Research Papers:

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 Ikegak and Hiroyuki Shimada _

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Oncotarget. 2018; 9:6416-6432. https://doi.org/10.18632/oncotarget.23740

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Abstract

Risa Niemas-Teshiba1, Ryosuke Matsuno1,13, Larry L. Wang1, Xao X. Tang2,14, Bill Chiu3, Jasmine Zeki3, Jeannine Coburn4, Kimberly Ornell4, Arlene Naranjo5, Collin Van Ryn5, Wendy B. London6, Michael D. Hogarty7, Julie M. Gastier-Foster8, A. Thomas Look9, Julie R. Park10, John M. Maris7, Susan L. Cohn11, Robert C. Seeger12, Shahab Asgharzadeh12, Naohiko Ikegaki2 and Hiroyuki Shimada1

1Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA

2Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA

3Department of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA

4Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, 01609, USA

5Department of Biostatistics, Children’s Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL 32607, USA

6Division of Hematology/Oncology, Boston Children’s Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA

7Division of Oncology and Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

8Institute of Genomic Medicine, Nationwide Children’s Hospital and Departments of Pathology and Pediatrics, Ohio State University College of Medicine, Columbus, OH 43210, USA

9Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA

10Department of Pediatrics, Seattle Children’s Hospital, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, WA 98105, USA

11Department of Pediatrics, Division of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA

12Division of Hematology/Oncology, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA

13Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama 1–30, Japan

14Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA

Correspondence to:

Hiroyuki Shimada, email: [email protected]

Naohiko Ikegaki, email: [email protected]

Keywords: nucleolar hypertrophy; protein translation; aminoacyl-tRNA synthetase; halofuginone; CX-5461

Received: August 16, 2017 Accepted: October 13, 2017 Published: December 15, 2017

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.


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