Sunandini Sharma, University of Nebraska Medical Center
Roshia Ali, University of Nebraska Medical Center
Alyssa Bouska, University of Nebraska Medical CenterFollow
Dylan T. Jochum, University of Nebraska Medical CenterFollow
Meghana Kesireddy, University of Nebraska Medical CenterFollow
Simeon Mahov, Cedars-Sinai Medical Center
Joseph Lownik, Cedars-Sinai Medical Center
Weiwei Zhang, University of Nebraska Medical CenterFollow
Waseem Lone, University of Nebraska Medical Center
Mahfuza Afroz Soma, University of Nebraska Medical CenterFollow
Alicia Gamboa, Cedars-Sinai Medical Center
Vaishnavi Devarakonda, Cedars-Sinai Medical Center
Dalia El-Gamal, University of Nebraska Medical Center
Atqiya Fariha, University of Nebraska Medical CenterFollow
Adnan Mansoor, University of Calgary
Douglas Stewart, University of Calgary
Peter Martin, Weill Cornell Medical College
Brian K. Link, University of Iowa Hospitals & Clinics
Ranjana H. Advani, Stanford Cancer Institute
Paul M. Barr, University of Rochester Medical Center
Andre H. Goy, John Theurer Cancer Center at Hackensack University Medical Center
Amitkumar Mehta, University of Alabama at Birmingham
Manali Kamdar, University of Colorado
Deborah M. Stephens, University of Utah
Veronika Bachanova, University of Minnesota
Lynette M. Smith, University of Nebraska Medical CenterFollow
Ryan Morin, Simon Fraser University
Prasath Pararajalingam, Simon Fraser University
Matthew A. Lunning, University of Nebraska Medical CenterFollow
Kai Fu, University of Nebraska Medical Center
Dennis D. Weisenburger, University of Nebraska Medical CenterFollow
Wing C. Chan, City of Hope National Medical Center
Joseph Khoury, University of Nebraska Medical CenterFollow
Timothy C. Greiner, University of Nebraska Medical Center
Julie M. Vose, University of Nebraska Medical CenterFollow
Akil Merchant, Cedars-Sinai Medical Center
Chengfeng Bi, University of Nebraska Medical CenterFollow
Javeed Iqbal, University of Nebraska Medical CenterFollow
North American Mantle Cell Lymphoma Project (NAMCLP)

Document Type

Article

Journal Title

Nature Communications

Publication Date

2025

Volume

16

Abstract

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.

MeSH Headings

Lymphoma, Mantle-Cell, Humans, Tumor Microenvironment, Prognosis, Tumor Suppressor Protein p53, Genomics, Ataxia Telangiectasia Mutated Proteins, Mutation, Female, Male, Middle Aged, Aged, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Rituximab

ISSN

2041-1723

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