Single Cell Resolution Tracking of Cutaneous T-Cell Lymphoma Reveals Clonal Evolution in Disease Progression

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Cutaneous T-cell lymphoma (CTCL) is a heterogeneous, therapy-resistant cancer with relentless progression.
• Multi-omics technologies offer precise insights into disease dynamics and treatment response.

Purpose of the Study:

• To comprehensively map the clonal evolution of CTCL using multi-omics data.
• To identify molecular underpinnings of CTCL progression at single-cell resolution.
• To discover novel biomarkers and therapeutic targets for CTCL.

Main Methods:

• Integrated analysis of exome, whole genome, epigenome, bulk, and single-cell (sc) VDJ/RNA sequencing from 114 patient samples.
• Single-cell resolution analysis of CTCL clonal evolution.
• CUT&RUN-seq to investigate STAT3 mutation effects on gene regulation.

Main Results:

• Identified recurrent genomic alterations associated with CTCL progression, including mutations in CCR4, PI3K signaling, and PD-1 checkpoint pathways.
• Discovered a STAT3 (D661Y) gain-of-function mutation enhancing Rho GTPase pathway gene binding.
• Found significant mutations in chromatin methylation modifiers (e.g., EZH2), suggesting EZH1/2 inhibition as a potential therapy.

Conclusions:

• CTCL progression involves complex clonal evolution driven by specific genomic alterations and pathway dysregulation.
• Rho GTPase pathway dysregulation and chromatin modifier mutations play critical roles in CTCL advancement.
• These molecular insights can guide improved disease monitoring, clinical trial design, and therapeutic strategies for CTCL.