LB884 Integrated transcriptome and trajectory analysis of cutaneous T-cell lymphoma identifies putative precancer populations

Cutaneous T-cell lymphoma (CTCL) incidence increases with age, and blood involvement portends a worse prognosis. To advance our understanding of CTCL development identify potential therapeutic targets, we performed integrative analyses paired single-cell RNA TCR sequencing peripheral CD4+ T-cells from patients to reveal disease unifying features. The malignant show highly diverse transcriptomic profiles across patients, most displaying mature Th2 differentiation exhaustion phenotype. TCR-CDR3 peptide prediction analysis showed limited diversity between samples, suggesting role for common antigenic stimulus. PHATE affinity-based transition identified putative precancerous circulating populations characterized by an intermediate stage gene expression mutation level the normal cells. We further revealed targeting CD82 JAK2 that endow cells survival proliferation advantages. found deficiency markedly reduced proliferative capacity activated apoptotic largely increased within CD82-knockout cultures. Both affected downstream signaling pathways differential enrichment highlighted JAK/STAT activation in determine if target specificity could improve JAK inhibitor activity patient-derived cell viability assays against panel FDA-approved agents exhibiting different family member selectivity profiles. exhibited marked preferential sensitivity JAK2-specific agents, relative JAK1/2-non-specific pan-JAK inhibitors, which suggested strategies JAK-2 may allow more generalized cytotoxic effects CTCL.