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. 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.

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Publication Details

Journal
Nature Communications
Published
2025-11-05
DOI
https://doi.org/10.1038/s41467-025-64666-7
Citations
1
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
1.47

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article

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

Manali Kamdar, Chengfeng Bi, Meghana Kesireddy, Wing C. Chan et al.
1 citations
Nature Communications
Lymphoma Diagnosis and Treatment
1.47
article

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

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

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.

Nature CommunicationsVol. 16(1)
Cedars-Sinai Medical Center (US), Roswell Park Comprehensive Cancer Center (US), City Of Hope National Medical Center (US), University of Minnesota (US), Nebraska Medical Center (US), Hackensack University Medical Center (US), University of Calgary (CA), Simon Fraser University (CA), Cornell University (US), University of Utah (US), Huntsman Cancer Institute (US), University of Iowa Hospitals and Clinics (US), University of Rochester Medical Center (US), University of Alabama at Birmingham (US), University of Minnesota Medical Center (US), Minnesota Oncology (US), Stanford Cancer Institute, University of Nebraska Medical Center (US), University of Colorado Denver (US)
Conquer Cancer Foundation, American Society of Clinical Oncology, University of Nebraska Medical Center, National Institutes of Health, National Cancer Institute
Openalex Percentile: Top 14%
Lymphoma Diagnosis and Treatment
1.47
DOIOpen Access PDFOpenAlex
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