Journal article
Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma
Nature communications, Vol.16(1), 9762
11/05/2025
DOI: 10.1038/s41467-025-64666-7
PMCID: PMC12589501
PMID: 41193463
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.
Details
- Title: Subtitle
- Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma
- Creators
- Sunandini Sharma - University of Nebraska Medical CenterRoshia Ali - University of Nebraska Medical CenterAlyssa Bouska - University of Nebraska Medical CenterDylan Jochum - University of Nebraska Medical CenterMeghana Kesireddy - University of Nebraska Medical CenterSimeon Mahov - Cedars-Sinai Medical CenterJoseph Lownik - Cedars-Sinai Medical CenterWeiwei Zhang - University of Nebraska Medical CenterWaseem Lone - University of Nebraska Medical CenterMahfuza Afroz Soma - University of Nebraska Medical CenterAlicia Gamboa - Cedars-Sinai Medical CenterVaishnavi Devarakonda - Cedars-Sinai Medical CenterDalia El-Gamal - University of Nebraska Medical CenterAtqiya Fariha - University of Nebraska Medical CenterAdnan Mansoor - University of CalgaryDouglas Stewart - University of CalgaryPeter Martin - Cornell UniversityBrian K Link - University of IowaRanjana H Advani - Stanford Cancer InstitutePaul M Barr - University of Rochester Medical CenterAndre H Goy - Hackensack University Medical CenterAmitkumar Mehta - University of Alabama at BirminghamManali Kamdar - University of Colorado DenverDeborah M Stephens - Huntsman Cancer InstituteVeronika Bachanova - University of MinnesotaLynette Smith - University of Nebraska Medical CenterRyan Morin - Simon Fraser UniversityPrasath Pararajalingam - Simon Fraser UniversityMatthew A Lunning - University of Nebraska Medical CenterKai Fu - Roswell Park Comprehensive Cancer CenterDennis Weisenburger - University of Nebraska Medical CenterWing C Chan - City Of Hope National Medical CenterJoseph Khoury - University of Nebraska Medical CenterTimothy C Greiner - University of Nebraska Medical CenterJulie M Vose - University of Nebraska Medical CenterAkil Merchant - Cedars-Sinai Medical CenterChengfeng Bi - University of Nebraska Medical CenterJaveed Iqbal - University of Nebraska Medical CenterNorth American Mantle Cell Lymphoma Project (NAMCLP)
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.16(1), 9762
- DOI
- 10.1038/s41467-025-64666-7
- PMID
- 41193463
- PMCID
- PMC12589501
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Springer Nature
- Grant note
- Conquer Cancer Foundation (Conquer Cancer Foundation of the American Society of Clinical Oncology)
The authors gratefully acknowledge the Lymphoma Study Group (LSG) and the Tissue Science Facility (TSF) at the University of Nebraska Medical Center (UNMC) for their expertise in paraffin sectioning, immunohistochemistry, and high-resolution slide scanning. The UNMC TSF is administered through the Department of Pathology and Microbiology and is supported in part by the Fred & Pamela Buffett Cancer Center's National Cancer Institute Cancer Support Grant. This project was supported by the American Cancer Society under award number IRG-18-240-04-IRG, the Fred & Pamela Buffett Cancer Center, supported by the National Cancer Institute under award number P30 CA036727 (C.B.), and the ASCO Conquer Cancer Frist Family Endowed Young Investigator Award (YIA) in Mantle Cell Lymphoma (M.Ke.). This work was also supported by the Nebraska Foundation and by NIH/NCI grants P01 CA229100, R01 CA036727 (J.I.), and R01 CA244900 (R.K.H.)
- Language
- English
- Date published
- 11/05/2025
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9985024248202771
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