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

doi:10.1016/j.celrep.2024.113938

A therapeutically targetable positive feedback loop between lnc-HLX-2-7, HLX, and MYC that promotes group 3 medulloblastoma

Cell Rep. 2024 Mar 26;43(3):113938. doi: 10.1016/j.celrep.2024.113938. Epub 2024 Mar 8.

Affiliations

¹ 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.
² Department of Medical and Molecular Sciences, University of Delaware, 15 Innovation Way, Newark, DE 19701, USA.
³ Johns Hopkins All Children's Hospital, 600 5th St. South, St. Petersburg, FL 33701, USA.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
⁸ Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross Bldg. 558, Baltimore, MD 21205, USA.
⁹ 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. Electronic address: jperera2@jh.edu.

PMID: 38460130
DOI: 10.1016/j.celrep.2024.113938

Abstract

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.

Keywords: CP: Cancer; CP: Neuroscience; eRNA; lnc-HLX-2-7; medulloblastoma; nanoparticles; therapeutics.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / genetics
Cerebellar Neoplasms* / drug therapy
Cerebellar Neoplasms* / genetics
Feedback
Gene Expression Regulation, Neoplastic
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Medulloblastoma* / genetics
Medulloblastoma* / pathology
Mice
Oncogenes
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Transcription Factors / metabolism

Substances

RNA, Long Noncoding
HLX protein, human
Transcription Factors
Homeodomain Proteins