Journal Article

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

Lone, Waseem, Kamdar, Manali, Stephens, Deborah M., Fariha, Atqiya, Chan, Wing C., Smith, Lynette, Merchant, Akil, Iqbal, Javeed, Mansoor, Adnan, Pararajalingam, Prasath, El-Gamal, Dalia, Bouska, Alyssa, Martin, Peter, Stewart, Douglas, Jochum, Dylan, Goy, Andre H., Kesireddy, Meghana, Bi, Chengfeng, Mehta, Amitkumar, Mahov, Simeon, Barr, Paul M., Weisenburger, Dennis, Soma, Mahfuza Afroz, Advani, Ranjana H., Ali, Roshia, Fu, Kai, Bachanova, Veronika, Zhang, Weiwei, Khoury, Joseph, Greiner, Timothy C., Lownik, Joseph, Link, Brian K., Gamboa, Alicia, Sharma, Sunandini, Vose, Julie M., Devarakonda, Vaishnavi, Morin, Ryan, Lunning, Matthew A.

2025

Overview

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. 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., IFNα, TNFα) 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 a dominant population of myeloid cells skewed toward an M2-like phenotype. Spatially, TP53 -perturbed MCLs are immune-infiltrated yet exhausted, while ATM -perturbed cases remain immune-cold with dense tumors. 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. Mantle cell lymphoma (MCL) is a form of B-cell non-Hodgkin lymphoma with a high degree of genetic and clinical heterogeneity. Here, using a multi-omics approach, the authors investigate genetic alterations in association with the tumour microenvironment to identify potential therapeutic vulnerabilities.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 45/91 / 631/67/1857 / 631/67/1990/291/1621/1915 / 692/4028/67/69 / Aged / Angiogenesis / Ataxia Telangiectasia Mutated Proteins - genetics / CD4 antigen / Cell cycle / Chemotherapy / Clinical outcomes / Cytometry / DNA damage / Enrichment / Epigenetics / Female / Functional analysis / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genes / Genomic analysis / Genomics / Heterogeneity / Hodgkin's lymphoma / Humanities and Social Sciences / Humans / Kinases / Lymphocytes / Lymphocytes B / Lymphocytes T / Lymphoma / Lymphoma, Mantle-Cell - drug therapy / Lymphoma, Mantle-Cell - genetics / Lymphoma, Mantle-Cell - immunology / Lymphoma, Mantle-Cell - pathology / Male / Malignancy / Mantle cell lymphoma / Middle Aged / multidisciplinary / Mutation / Myeloid cells / p53 Protein / Phenotypes / Prognosis / Proteomics / Risk / Rituximab / Rituximab - therapeutic use / Science / Science (multidisciplinary) / Transcriptomics / Transplants & implants / Tumor microenvironment / Tumor Microenvironment - genetics / Tumor Suppressor Protein p53 - genetics / Tumors / α-Interferon