Dominant Malignant Clones Leverage Lineage Restricted Epigenomic Programs to Drive Ependymoma Development

Area of Science:

• Neuro-oncology
• Developmental biology
• Epigenetics

Background:

• ZFTA-RELA gene fusions are the most common genetic alteration in pediatric supratentorial ependymoma (EPN).
• This fusion protein is sufficient to initiate tumor formation in mice, but its specific cellular targets during development remain unclear.

Purpose of the Study:

• To identify specific developmental cell lineage programs at risk of transformation by ZFTA-RELA.
• To investigate the role of developmental chromatin accessibility in ZFTA-RELA driven ependymoma.

Main Methods:

• Combined single-cell ATAC and RNA-seq (scMultiome) analysis of developing mouse forebrain and ZFTA-RELA driven mouse and human ependymoma.
• In vivo lineage tracing studies.

Main Results:

• Specific developmental lineage programs in radial glial cells, regulated by Plagl transcription factors, are susceptible to neoplastic transformation.
• ZFTA-RELA binding leads to persistent chromatin accessibility and oncogene expression at specific loci.
• Cross-species analysis revealed cell type heterogeneity in EPN, with intermediate progenitor-like cells forming a tumor hierarchy.
• Dominant neoplastic clones were identified that drive tumor growth and establish the entire cellular hierarchy.

Conclusions:

• Developmental epigenomic states are critical for fusion oncoprotein-driven transformation in pediatric ependymoma.
• Distinct lineage differentiation programs, influenced by chromatin accessibility, dictate oncogenic transformation risk.
• Early progenitor-like cells establish the EPN tumor hierarchy, mirroring normal neural differentiation.