Genomic Aberrations Generate Fusion Gene FOXK2::TP63 and Activate NFKB1 in Cutaneous T-Cell Lymphoma

Area of Science:

• Genetics and Genomics
• Oncology
• Molecular Biology

Background:

• Cutaneous T-cell lymphoma (CTCL) is a severe lymphoid malignancy with poor prognosis and limited curative options.
• NFkB signaling pathway dysregulation is implicated in CTCL pathogenesis.
• Previous studies identified mutations like in NFKB2 in CTCL cell lines.

Purpose of the Study:

• To identify additional genetic aberrations driving gene deregulation in CTCL cell lines.
• To investigate the functional roles of identified genetic alterations in CTCL.
• To explore potential therapeutic targets for CTCL.

Main Methods:

• Karyotyping and genomic profiling of CTCL cell lines (HUT-78 and HH).
• RNA-sequencing (RNA-seq) and Polymerase Chain Reaction (PCR) analysis.
• Transcription factor binding-site analysis, siRNA-mediated knockdown, and inhibitor treatments.

Main Results:

• A novel fusion gene, FOXK2::TP63, was identified in HH cells due to t(3;17)(q28;q25).
• Aberrant NFKB1 overexpression linked to amplification at 4q24-26, with IRF4 contributing to its expression.
• Amplifications of CAMK2D and UBE2D3 were found within the 4q amplicon; NFKB2 deletion in HUT-78.
• NFkB inhibition affected proliferation, and NOTCH pathway inhibition (DAPT) improved survival in HH cells.

Conclusions:

• NFkB and NOTCH pathways are critical for CTCL cell proliferation and survival.
• Identified genetic aberrations like FOXK2::TP63 fusion and NFKB1 overexpression contribute to CTCL.
• NFkB and/or NOTCH inhibitors represent potential therapeutic strategies for CTCL patients.