Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone.TP53alterations were consistently associated with poor prognosis, whereasATMmutations correlated with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters were identified and refined into three prognostic groups: high-risk (TP53mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATMand epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lackingTP53alterations, rareATMmutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis revealed enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFNα, TNFα) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrated enrichment of CD8⁺ T cells with high expression of exhaustion markers and dominant population of myeloid cells skewed toward an M2-like phenotype. Compared toATM-perturbed tumors,TP53-perturbed tumors exhibited enriched SOX11⁺ tumor cells and enhanced tumor-immune cell interactions. Functional analysis revealed that p53 represses BCR signaling throughPTPN6activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-riskTP53-altered MCL.