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

Keisuke Katsushima1, Kandarp Joshi1, Menglang Yuan1

  • 1Department 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.

Cell Reports
|March 9, 2024
PubMed

Insights

A newly identified long non-coding RNA, lnc-HLX-2-7, drives group 3 medulloblastoma (G3 MB) progression. Targeting this RNA with nanoparticles significantly inhibits tumor growth and enhances survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in cancer development.
  • Group 3 medulloblastoma (G3 MB) is an aggressive pediatric brain tumor with limited therapeutic options.

Purpose of the Study:

  • To investigate the role of lnc-HLX-2-7 in G3 MB pathogenesis.
  • To evaluate lnc-HLX-2-7 as a potential therapeutic target for G3 MB.

Main Methods:

  • RNA sequencing and chromatin immunoprecipitation were used to identify and characterize the lnc-HLX-2-7 regulatory pathway.
  • In vivo studies utilized an intracranial G3 MB xenograft mouse model treated with cerium-oxide-nanoparticle-coated antisense oligonucleotides (CNP-lnc-HLX-2-7).

Main Results:

  • lnc-HLX-2-7 was found to activate the oncogene HLX by recruiting enhancer elements.
  • HLX was shown to activate key oncogenes including MYC, LIN9, TBX2, and HOXM1.
  • CNP-lnc-HLX-2-7 treatment reduced tumor growth by 40%-50% in a mouse model.
  • Combination therapy with CNP-lnc-HLX-2-7 and cisplatin significantly improved survival.

Conclusions:

  • The lnc-HLX-2-7-HLX-MYC axis is a critical regulator of G3 MB progression.
  • lnc-HLX-2-7 represents a promising therapeutic target for G3 MB.

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