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<p>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. <i>TP53</i> alterations are consistently associated with poor prognosis, whereas <i>ATM</i> 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 (<i>TP53</i> mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (<i>ATM</i> and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking <i>TP53</i> alterations, rare <i>ATM</i> 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, <i>TP53</i>-perturbed MCLs are immune-infiltrated&#xa0;yet exhausted, while <i>ATM</i>-perturbed cases remain immune-cold with dense tumors. Functional analysis shows that p53 represses BCR signaling through <i>PTPN6</i> activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk <i>TP53</i>-perturbed MCL.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月5日

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

摘要

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.