Functional Genomics and Tumor Microenvironment Analysis Reveal Prognostic Biological Subtypes in Mantle Cell Lymphoma [RNA-seq]
Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We study two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations are consistently associated with poor prognosis, whereas ATM mutations correlate with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters are identified and refined into three prognostic groups: high-risk (TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis reveals enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFNa, TNFa) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrates enrichment of CD4? T cells with high expression of exhaustion markers and dominant population of myeloid cells skewed toward an M2-like phenotype. Spatially, TP53-perturbed MCLs are immune infiltrated but exhausted, while ATM-perturbed cases remain immune-cold with dense tumor. Functional analysis shows that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53-perturbed MCL. Overall design: 47/51 Human  formalin-fixed paraffin-embedded (FFPE) MCL samples were used for RNA-Seq analysis. The samples were annotated into different genomic clusters and Gene Set Enrichment Analysis (GSEA) was performed to show enrichment in different biological pathways. These samples were also used for Gene Expression Profile (GEP) and copy number alterations (CNAs) analysis.