A therapeutically targetable positive feedback loop between lnc-HLX-2-7, HLX, and MYC that promotes group 3 medulloblastoma
Keisuke Katsushima,
Kandarp Joshi,
Menglang Yuan,
Brigette Romero,
Mona Batish,
Stacie Stapleton,
George Jallo,
Elayaraja Kolanthai,
Sudipta Seal,
Olivier Saulnier,
Michael D. Taylor,
Robert J. Wechsler-Reya,
Charles G. Eberhart,
Ranjan J. Perera
Affiliations
Keisuke Katsushima
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21231, USA; Johns Hopkins All Children’s Hospital, 600 5th St. South, St. Petersburg, FL 33701, USA
Kandarp Joshi
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21231, USA; Johns Hopkins All Children’s Hospital, 600 5th St. South, St. Petersburg, FL 33701, USA
Menglang Yuan
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21231, USA; Johns Hopkins All Children’s Hospital, 600 5th St. South, St. Petersburg, FL 33701, USA
Brigette Romero
Department of Medical and Molecular Sciences, University of Delaware, 15 Innovation Way, Newark, DE 19701, USA
Mona Batish
Department of Medical and Molecular Sciences, University of Delaware, 15 Innovation Way, Newark, DE 19701, USA
Stacie Stapleton
Johns Hopkins All Children’s Hospital, 600 5th St. South, St. Petersburg, FL 33701, USA
George Jallo
Johns Hopkins All Children’s Hospital, 600 5th St. South, St. Petersburg, FL 33701, USA
Elayaraja Kolanthai
Advanced Materials Processing and Analysis Center, Nanoscience and Technology Center, Materials Science and Engineering, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
Sudipta Seal
Advanced Materials Processing and Analysis Center, Nanoscience and Technology Center, Materials Science and Engineering, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
Olivier Saulnier
Genomics and Development of Childhood Cancers, Institut Curie, PSL University, 75005 Paris, France; INSERM U830, Cancer Heterogeneity Instability and Plasticity, Institut Curie, PSL University, 75005 Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, 75005 Paris, France
Michael D. Taylor
Texas Children’s Cancer Center, Hematology-Oncology Section, Houston, TX 77004, USA; Department of Pediatrics – Hematology/Oncology and Neurosurgery, Baylor College of Medicine, Houston, TX 77004, USA
Robert J. Wechsler-Reya
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA
Charles G. Eberhart
Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross Bldg. 558, Baltimore, MD 21205, USA
Ranjan J. Perera
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21231, USA; Johns Hopkins All Children’s Hospital, 600 5th St. South, St. Petersburg, FL 33701, USA; Corresponding author
Summary: Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma (MB) formation and progression. We have identified an lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) MBs. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, a sense-overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium-oxide-nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40%–50% in an intracranial MB xenograft mouse model. Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy. Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 MB progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs.
