Single-cell and bulk transcriptomic integration identifies a high-CNV, dark-zone-enriched malignant cell state associated with adverse prognosis in GCB-DLBCL

A high-CNV compartment displayed dark-zone-like transcriptional programmes, enrichment of proliferation- and survival-associated features, and reduced antigen-presentation capacity. Subclustering resolved three malignant states, among which M-C2 showed the highest inferred CNV burden and a distinct germinal-centre regulatory programme marked by enhanced BCL6, TCF3, and PAX5 activity. M-C2 was enriched for DLBCL susceptibility-associated signals, and its higher abundance was consistently associated with inferior overall survival across independent bulk cohorts.

Integrative prioritisation identified an eight-gene M-C2-associated panel comprising IRF4, AKT1S1, PIEZO1, POLR1A, EML6, TTN, FCRL5, and IGHG2. An exploratory prognostic model integrating molecular and clinical features further supported the potential predictive value of this programme.</p> <p>This study identifies a high-CNV, dark-zone-enriched malignant cell state within GCB-DLBCL, represented by the M-C2 subpopulation, associated with impaired antigen presentation and adverse prognosis.

This framework improves understanding of malignant heterogeneity and warrants further validation for risk stratification.</p>