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1
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Du MQ. EMZL at various sites: learning from each other. Blood 2025; 145:2117-2127. [PMID: 39912633 DOI: 10.1182/blood.2024025794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 02/07/2025] Open
Abstract
ABSTRACT Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) invariably develops from a background of chronic inflammatory disorder caused by a diverse chronic microbial infection and/or autoimmunity, depending on the site. These chronic inflammatory/autoimmunity disorders trigger innate and acquired immune responses, generating a unique microenvironment at each site that drives clonal evolution of B cells, their expansion, and eventual malignant transformation. At a molecular level, this involves temporal and spatial acquisition of cooperative oncogenic events by dysregulated immune responses and somatic genetic changes. Although these events are not yet fully characterized, EMZL at several sites shows distinct genetic profiles and molecular insights, bridging the pathologic process to lymphomagenesis. For example, gastric EMZL, particularly those lacking a BCL10 or MALT1 translocation, critically depends on T-helper cell signals produced by immune responses to Helicobacter pylori infection. Likewise, thyroid EMZL may also involve exaggerated T-cell help because of highly frequent inactivating mutations in TET2, CD274 (programmed cell death 1 ligand 1), and TNFRSF14, which impede the coinhibitory interactions between the neoplastic B- and T-helper cells, thus releasing T-cell help. Ocular adnexal EMZL shows frequent TNFAIP3 (A20) mutation/deletion that significantly associates with expression of autoreactive IGHV4-34 B-cell receptor, emphasizing its potential cooperation in NF-κB pathway activation. Finally, the genesis of salivary gland EMZL may be closely associated with GPR34 activation that is caused by mutation/t(X;14)(p11;q32) and/or paracrine stimulation mediated by ligand generated by lymphoepithelial lesions. This review will focus on these novel molecular insights and how these advances may provide a paradigm for future investigations.
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MESH Headings
- Humans
- Lymphoma, B-Cell, Marginal Zone/pathology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/immunology
- Lymphoma, B-Cell, Marginal Zone/metabolism
- Lymphoma, B-Cell, Marginal Zone/etiology
- Animals
- Helicobacter Infections/immunology
- Helicobacter Infections/complications
- Helicobacter Infections/pathology
- Helicobacter pylori
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Affiliation(s)
- Ming-Qing Du
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
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Peng T, Liu J, Zhao H. Preliminary Observations of a Substrate-Based Radiotracer Biosensor for In Vivo Positron Emission Tomography Imaging of Tumor Transmembrane Protease ST14. ACS Sens 2025; 10:2768-2778. [PMID: 40233018 DOI: 10.1021/acssensors.4c03476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Imaging protease proteolysis with positron emission tomography (PET) has not been well documented in the literature, primarily due to the absence of suitable radiotracers. This study aims to develop a substrate-based radiotracer biosensor for ST14 protease to facilitate direct in vivo PET imaging of proteolysis. The design of the substrate-based radiotracer RQARK-DOTA-68Ga is characterized by the inclusion of an ST14 substrate RQAR moiety and a Lys-DOTA-68Ga moiety, linked via an ST14 cleavage site. The enzymatic cleavage of this radiotracer by ST14 protease was characterized in vitro, and the proteolysis of ST14 was further confirmed through in vivo PET imaging in tumors expressing ST14. RQARK-DOTA-68Ga was specifically cleaved by ST14 protease to yield Lys-DOTA-68Ga and RQAR moieties, whereas the d-isomer, rqark-DOTA-68Ga, was not susceptible to cleavage by ST14 protease. In vivo PET imaging demonstrated high tumor uptake of radioactive signal postinjection RQARK-DOTA-68Ga in ST14-expressing AsPC-1 xenografts, with optimal accumulation observed 1 h postinjection. In contrast, the d-isomer radiotracer, rqark-DOTA-68Ga, exhibited negligible tumor uptake, indicating a distinct preference for the substrate-based radiotracer in regions of ST14-mediated proteolysis. Radio-HPLC analysis following extraction from AsPC-1 tumors injected with RQARK-DOTA-68Ga identified a radioactive peak corresponding to Lys-DOTA-68Ga, confirming enzymatic cleavage and the generation of the anticipated radioactive product in the tumor tissue. Preliminary results indicate that a novel strategy for noninvasive in vivo positron emission tomography imaging of the transmembrane protease ST14 in tumors has been introduced through the development and application of a substrate-based radiotracer biosensor. The radiotracer RQARK-DOTA-68Ga, capable of producing imaging signals through structural changes triggered by substrate cleavage, has proven its ST14-targeting potency in both in vitro enzymatic assays and in vivo PET imaging.
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Affiliation(s)
- Tukang Peng
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 210000, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 210000, China
| | - Haitao Zhao
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 210000, China
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3
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Zhang RY, Wang ZX, Zhang MY, Wang YF, Zhou SL, Xu JL, Lin WX, Ji TR, Chen YD, Lu T, Li NG, Shi ZH. MALT1 Inhibitors and Degraders: Strategies for NF-κB-Driven Malignancies. J Med Chem 2025; 68:5075-5096. [PMID: 39999563 DOI: 10.1021/acs.jmedchem.4c02873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2025]
Abstract
Mucosa-associated lymphoid tissue protein 1 (MALT1), a cysteine protease and the sole paracaspase in humans, plays a pivotal role in the survival and proliferation of NF-κB-dependent malignant cancers, particularly MALT lymphoma and diffuse large B-cell lymphoma (DLBCL). Dysregulated MALT1 activity is implicated in various malignancies, highlighting its importance as a therapeutic target. This Perspective provides an overview of MALT1's structural and functional characteristics, summarizes recent advancements in small-molecule inhibitors and degraders targeting this protein, and discusses compound structures, structure-activity relationship (SAR) analyses, and biological activities. We aim to inform future research efforts to enhance the activity, selectivity, and pharmacological properties of MALT1-targeting compounds, establishing a foundational framework for drug development in this critical area of cancer therapy.
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Affiliation(s)
- Ru-Yue Zhang
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Zi-Xuan Wang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China
| | - Meng-Yuan Zhang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China
| | - Yu-Fan Wang
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Si-Li Zhou
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Jia-Lu Xu
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Wen-Xuan Lin
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Tian-Rui Ji
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Ya-Dong Chen
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Tao Lu
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
| | - Nian-Guang Li
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China
| | - Zhi-Hao Shi
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China
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Liu H, Wang J, Zhang W, Zhao X, Jin H. AjMALT1 promotes Vibrio splendidus-induced inflammation through the NF-κB pathway in Apostichopus japonicus. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 165:105346. [PMID: 39984065 DOI: 10.1016/j.dci.2025.105346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/16/2025] [Accepted: 02/18/2025] [Indexed: 02/23/2025]
Abstract
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), an intracellular signaling molecule, is widely expressed during inflammatory responses. To investigate the immune function of AjMALT1 in Apostichopus japonicus, the full length of AjMALT1 gene was cloned using transcriptome data and RACE technology. The results showed that AjMALT1 was distributed in all tissues, with higher expression found in coelomocytes and intestine. The expression of AjMALT1 was significantly upregulated in Vibrio splendidus-challenged sea cucumbers, as well as in coelomocytes exposed to inactive V. splendidus, and was positively correlated with the expression of the pro-inflammatory cytokine AjIL17 and the inflammasome component AjNLRP3. Further investigation using specific siRNA to silence AjMALT1 for 48 h revealed that the expression of AjIL17 and AjNLRP3 was reduced under V. splendidus stimulation. Additionally, histological observations showed a decrease in intestinal inflammation. Interference with AjMALT1 also led to downregulation of AjTRAF6 and AjRel expression, as well as inhibited nuclear translocation of AjRel. These findings suggest AjMALT1 exacerbates intestinal and coelomic inflammation by activating the AjTRAF6-dependent NF-κB pathway in A. japonicus.
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Affiliation(s)
- Haiping Liu
- Key Laboratory of Aquacultural Biotechnology (Ningbo University), Ministry of Education, Ningbo, 315800, PR China
| | - Jiping Wang
- Key Laboratory of Aquacultural Biotechnology (Ningbo University), Ministry of Education, Ningbo, 315800, PR China
| | - Weiwei Zhang
- Key Laboratory of Aquacultural Biotechnology (Ningbo University), Ministry of Education, Ningbo, 315800, PR China
| | - Xuelin Zhao
- Key Laboratory of Aquacultural Biotechnology (Ningbo University), Ministry of Education, Ningbo, 315800, PR China.
| | - Heng Jin
- School of Mechatronics and Energy Engineering, NingboTech University, Ningbo, 315000, PR China
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Zhang Q, Yan W, Li H, Peng H. Advances in the Pathogenesis, Diagnosis, Treatment, and Prognosis of Marginal Zone Lymphoma. Curr Treat Options Oncol 2025; 26:142-155. [PMID: 39891871 DOI: 10.1007/s11864-025-01293-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2025] [Indexed: 02/03/2025]
Abstract
OPINION STATEMENT The management of marginal zone lymphoma (MZL), an indolent B-cell non-Hodgkin lymphoma, requires a personalized and adaptive approach due to its clinical and prognostic heterogeneity. We believe treatment should emphasize a balanced strategy considering the subtype, disease burden, symptoms, and actionable genetic or environmental factors, such as infections or autoimmune diseases. For asymptomatic patients with low tumor burden or disseminated disease, a watch-and-wait approach remains appropriate, given MZL's indolent nature and the risks of overtreatment. Conversely, for symptomatic or high-burden cases, early intervention with chemoimmunotherapy is recommended for effective disease control. Surgery remains essential for both diagnosis and the treatment of localized disease. Incorporating molecular profiling and prognostic models, such as MZL-IPI and POD24, is crucial for decision-making and risk stratification. Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients. With ongoing advancements in understanding dysregulated signaling pathways and the tumor microenvironment, we anticipate novel targeted therapies and combination regimens will further improve outcomes. We advocate for molecular testing at diagnosis to identify actionable biomarkers, particularly for patients with refractory or relapsed disease. Finally, MZL management requires vigilant follow-up with adjustments based on evolving disease features. Treatment decisions should integrate patient preferences, clinical context, and the latest evidence to maximize survival while preserving quality of life.
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Affiliation(s)
- Qingyang Zhang
- Department of Hematology, The Second Xiangya Hospital, Central South University, No.139th Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Wenzhe Yan
- Department of Hematology, The Second Xiangya Hospital, Central South University, No.139th Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Heng Li
- Department of Hematology, The Second Xiangya Hospital, Central South University, No.139th Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Hongling Peng
- Department of Hematology, The Second Xiangya Hospital, Central South University, No.139th Renmin Middle Road, Changsha, 410011, Hunan, China.
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, 410011, Hunan, China.
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Rodriguez BN, Huang H, Chia JJ, Hoffmann A. The noncanonical NFκB pathway: Regulatory mechanisms in health and disease. WIREs Mech Dis 2024; 16:e1646. [PMID: 38634218 PMCID: PMC11486840 DOI: 10.1002/wsbm.1646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 04/19/2024]
Abstract
The noncanonical NFκB signaling pathway mediates the biological functions of diverse cell survival, growth, maturation, and differentiation factors that are important for the development and maintenance of hematopoietic cells and immune organs. Its dysregulation is associated with a number of immune pathologies and malignancies. Originally described as the signaling pathway that controls the NFκB family member RelB, we now know that noncanonical signaling also controls NFκB RelA and cRel. Here, we aim to clarify our understanding of the molecular network that mediates noncanonical NFκB signaling and review the human diseases that result from a deficient or hyper-active noncanonical NFκB pathway. It turns out that dysregulation of RelA and cRel, not RelB, is often implicated in mediating the resulting pathology. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Cancer > Molecular and Cellular Physiology Immune System Diseases > Stem Cells and Development.
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Affiliation(s)
- Benancio N. Rodriguez
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Molecular Biology Institute, Los Angeles, CA
| | - Helen Huang
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Institute for Quantitative and Computational Biosciences, Los Angeles, CA
| | - Jennifer J. Chia
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Molecular Biology Institute, Los Angeles, Calif; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular Genetics; Molecular Biology Institute; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA
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7
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Fischbach W, Eck M, Rosenwald A. From modern pathogenetic insights and molecular understanding to new deescalating therapeutic strategies in gastric MALT-lymphoma. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1952-1962. [PMID: 39321967 DOI: 10.1055/a-2382-7820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
Based on new insights into the aetiology and pathogenesis of gastric marginal-zone B-cell lymphoma of MALT (MALT-lymphoma) and its histomorphological and molecular characteristics, important progress in our understanding of the disease and its clinical management has been made during the last decades. A landmark in this development was the identification of Helicobacter pylori as the decisive pathogenetic factor for gastric MALT lymphoma. We, here, give an overview about the history and the current knowledge of the histology, genetics, and molecular characteristics and pathogenesis of gastric MALT lymphoma. We then focus on how these findings have fundamentally changed its clinical management over the last three decades with consequent deescalating therapeutic strategies.
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Affiliation(s)
- Wolfgang Fischbach
- Gastroenterologische Gemeinschaftspraxis Aschaffenburg, Klinikum Aschaffenburg-Alzenau, Academic Teaching Hospital of the University of Würzburg, Aschaffenburg, Germany
| | - Matthias Eck
- Institute of Pathology, Klinikum Aschaffenburg-Alzenau, Academic Teaching Hospital of the University of Würzburg, Aschaffenburg, Germany
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8
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Moud BN, Ober F, O’Neill TJ, Krappmann D. MALT1 substrate cleavage: what is it good for? Front Immunol 2024; 15:1412347. [PMID: 38863711 PMCID: PMC11165066 DOI: 10.3389/fimmu.2024.1412347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 05/07/2024] [Indexed: 06/13/2024] Open
Abstract
CARD-BCL10-MALT1 (CBM) signalosomes connect distal signaling of innate and adaptive immune receptors to proximal signaling pathways and immune activation. Four CARD scaffold proteins (CARD9, 10, 11, 14) can form seeds that nucleate the assembly of BCL10-MALT1 filaments in a cell- and stimulus-specific manner. MALT1 (also known as PCASP1) serves a dual function within the assembled CBM complexes. By recruiting TRAF6, MALT1 acts as a molecular scaffold that initiates IκB kinase (IKK)/NF-κB and c-Jun N-terminal kinase (JNK)/AP-1 signaling. In parallel, proximity-induced dimerization of the paracaspase domain activates the MALT1 protease which exerts its function by cleaving a set of specific substrates. While complete MALT1 ablation leads to immune deficiency, selective destruction of either scaffolding or protease function provokes autoimmune inflammation. Thus, balanced MALT1-TRAF6 recruitment and MALT1 substrate cleavage are critical to maintain immune homeostasis and to promote optimal immune activation. Further, MALT1 protease activity drives the survival of aggressive lymphomas and other non-hematologic solid cancers. However, little is known about the relevance of the cleavage of individual substrates for the pathophysiological functions of MALT1. Unbiased serendipity, screening and computational predictions have identified and validated ~20 substrates, indicating that MALT1 targets a quite distinct set of proteins. Known substrates are involved in CBM auto-regulation (MALT1, BCL10 and CARD10), regulation of signaling and adhesion (A20, CYLD, HOIL-1 and Tensin-3), or transcription (RelB) and mRNA stability/translation (Regnase-1, Roquin-1/2 and N4BP1), indicating that MALT1 often targets multiple proteins involved in similar cellular processes. Here, we will summarize what is known about the fate and functions of individual MALT1 substrates and how their cleavage contributes to the biological functions of the MALT1 protease. We will outline what is needed to better connect critical pathophysiological roles of the MALT1 protease with the cleavage of distinct substrates.
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Affiliation(s)
| | | | | | - Daniel Krappmann
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
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9
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Juilland M, Alouche N, Ubezzi I, Gonzalez M, Rashid HO, Scarpellino L, Erdmann T, Grau M, Lenz G, Luther SA, Thome M. Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination. Proc Natl Acad Sci U S A 2023; 120:e2301155120. [PMID: 38109544 PMCID: PMC10756297 DOI: 10.1073/pnas.2301155120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 10/24/2023] [Indexed: 12/20/2023] Open
Abstract
The protease MALT1 promotes lymphocyte activation and lymphomagenesis by cleaving a limited set of cellular substrates, most of which control gene expression. Here, we identified the integrin-binding scaffold protein Tensin-3 as a MALT1 substrate in activated human B cells. Activated B cells lacking Tensin-3 showed decreased integrin-dependent adhesion but exhibited comparable NF-κB1 and Jun N-terminal kinase transcriptional responses. Cells expressing a noncleavable form of Tensin-3, on the other hand, showed increased adhesion. To test the role of Tensin-3 cleavage in vivo, mice expressing a noncleavable version of Tensin-3 were generated, which showed a partial reduction in the T cell-dependent B cell response. Interestingly, human diffuse large B cell lymphomas and mantle cell lymphomas with constitutive MALT1 activity showed strong constitutive Tensin-3 cleavage and a decrease in uncleaved Tensin-3 levels. Moreover, silencing of Tensin-3 expression in MALT1-driven lymphoma promoted dissemination of xenografted lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage reveals a unique aspect of the function of MALT1, which negatively regulates integrin-dependent B cell adhesion and facilitates metastatic spread of B cell lymphomas.
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Affiliation(s)
- Mélanie Juilland
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Nagham Alouche
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Ivana Ubezzi
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Montserrat Gonzalez
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Harun-Or Rashid
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Leonardo Scarpellino
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Tabea Erdmann
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Münster, MünsterD-48149, Germany
| | - Michael Grau
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Münster, MünsterD-48149, Germany
| | - Georg Lenz
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Münster, MünsterD-48149, Germany
| | - Sanjiv A. Luther
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Margot Thome
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
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Wimberger N, Ober F, Avar G, Grau M, Xu W, Lenz G, Menden MP, Krappmann D. Oncogene-induced MALT1 protease activity drives posttranscriptional gene expression in malignant lymphomas. Blood 2023; 142:1985-2001. [PMID: 37623434 PMCID: PMC10733837 DOI: 10.1182/blood.2023021299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/13/2023] [Accepted: 07/26/2023] [Indexed: 08/26/2023] Open
Abstract
Constitutive mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) activity drives survival of malignant lymphomas addicted to chronic B-cell receptor signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. Although MALT1 scaffolding induces NF-κB-dependent survival signaling, MALT1 protease function is thought to augment NF-κB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-κB transcriptional responses but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and nonenzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease-dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. The data suggest that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces posttranscriptional upregulation of many genes including NFKBIZ/IκBζ, NFKBID/IκBNS, and ZC3H12A/Regnase-1 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on an mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives posttranscriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in MALT lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and posttranscriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease-selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.
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Affiliation(s)
- Nicole Wimberger
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets Therapeutic Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Franziska Ober
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets Therapeutic Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Göksu Avar
- Department of Computational Health, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Biology, Ludwig Maximilian University Munich, Martinsried, Germany
| | - Michael Grau
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Muenster, Muenster, Germany
| | - Wendan Xu
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Muenster, Muenster, Germany
| | - Georg Lenz
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Muenster, Muenster, Germany
| | - Michael P. Menden
- Department of Computational Health, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Biology, Ludwig Maximilian University Munich, Martinsried, Germany
- Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Australia
| | - Daniel Krappmann
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets Therapeutic Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Biology, Ludwig Maximilian University Munich, Martinsried, Germany
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11
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Verhelst SHL, Prothiwa M. Chemical Probes for Profiling of MALT1 Protease Activity. Chembiochem 2023; 24:e202300444. [PMID: 37607867 DOI: 10.1002/cbic.202300444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/20/2023] [Accepted: 08/22/2023] [Indexed: 08/24/2023]
Abstract
The paracaspase MALT1 is a key regulator of the human immune response. It is implicated in a variety of human diseases. For example, deregulated protease activity drives the survival of malignant lymphomas and is involved in the pathophysiology of autoimmune/inflammatory diseases. Thus, MALT1 has attracted attention as promising drug target. Although many MALT1 inhibitors have been identified, molecular tools to study MALT1 activity, target engagement and inhibition in complex biological samples, such as living cells and patient material, are still scarce. Such tools are valuable to validate MALT1 as a drug target in vivo and to assess yet unknown biological roles of MALT1. In this review, we discuss the recent literature on the development and biological application of molecular tools to study MALT1 activity and inhibition.
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Affiliation(s)
- Steven H L Verhelst
- Department of Cellular and Molecular Medicine, KU Leuven - University of Leuven, Herestraat 49, box 901b, 3000, Leuven, Belgium
- Leibniz Institut für Analytische Wissenschaften - ISAS - e.V., Otto-Hahn Strasse 6b, 44227, Dortmund, Germany
| | - Michaela Prothiwa
- Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
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12
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Guldenpfennig C, Teixeiro E, Daniels M. NF-kB's contribution to B cell fate decisions. Front Immunol 2023; 14:1214095. [PMID: 37533858 PMCID: PMC10391175 DOI: 10.3389/fimmu.2023.1214095] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/03/2023] [Indexed: 08/04/2023] Open
Abstract
NF-κB signaling is essential to an effective innate and adaptive immune response. Many immune-specific functional and developmental outcomes depend in large on NF-κB. The formidable task of sorting out the mechanisms behind the regulation and outcome of NF-κB signaling remains an important area of immunology research. Here we briefly discuss the role of NF-κB in regulating cell fate decisions at various times in the path of B cell development, activation, and the generation of long-term humoral immunity.
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Affiliation(s)
- Caitlyn Guldenpfennig
- Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
| | - Emma Teixeiro
- Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
| | - Mark Daniels
- Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
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13
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Raderer M, Kiesewetter B, Du MQ. Clinical relevance of molecular aspects in extranodal marginal zone lymphoma: a critical appraisal. Ther Adv Med Oncol 2023; 15:17588359231183565. [PMID: 37389189 PMCID: PMC10302523 DOI: 10.1177/17588359231183565] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 05/24/2023] [Indexed: 07/01/2023] Open
Abstract
Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) is among the more common types of lymphoma accounting for up to 8% of newly diagnosed lymphoma cases. As opposed to other B-cell lymphomas, however, no predominant genetic hallmark has been defined in MALT lymphoma, but different localizations appear to be affected by different, sometimes distinct changes. Nonetheless, a high proportion of these genetic changes reported in MALT lymphomas dysregulate the pathways leading to NF-kB activation. t(11;18)(q21;q21)/BIRC3::MALT1 appears to be MALT lymphoma specific and is found in 24% of gastric and 40% of pulmonary MALT lymphomas. The translocation is associated with more disseminated disease in gastric MALT lymphoma and is found in a large percentage of patients whose lymphoma is unresponsive to antibiotic eradication of Helicobacter pylori. In addition to t(11;18)(q21;q21), nuclear expression of BCL10 or NF-kB appears to be highly associated with lymphoma cell survival independence of H. pylori-mediated stimulations. Antibiotic eradication, however, is the recommended therapy of choice irrespective of genetic findings, and molecular analysis is not required before initiation of therapy. The influence of genetic translocations including t(11;18)(q21;q21) on systemic therapies, however, is less clearly defined. While small series have shown no influence on the outcome for treatment with the anti-CD20 antibody rituximab (R) or treatment with cladribine (2-CdA), conflicting data have been reported for alkylating agents, especially chlorambucil and the combination of R + chlorambucil. None of other genetic changes seen in MALT lymphoma to date has discernible value in routine clinical applications, but recent data suggest that changes in TNFAIP3(A20), KMTD2 and CARD11 might be associated with response to Bruton kinase inhibitors.
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Affiliation(s)
| | - Barbara Kiesewetter
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
| | - Ming-Qing Du
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK
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14
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O'Neill TJ, Tofaute MJ, Krappmann D. Function and targeting of MALT1 paracaspase in cancer. Cancer Treat Rev 2023; 117:102568. [PMID: 37126937 DOI: 10.1016/j.ctrv.2023.102568] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 05/03/2023]
Abstract
The paracaspase MALT1 has emerged as a key regulator of immune signaling, which also promotes tumor development by both cancer cell-intrinsic and -extrinsic mechanisms. As an integral subunit of the CARD11-BCL10-MALT1 (CBM) signaling complex, MALT1 has an intriguing dual function in lymphocytes. MALT1 acts as a scaffolding protein to drive activation of NF-κB transcription factors and as a protease to modulate signaling and immune activation by cleavage of distinct substrates. Aberrant MALT1 activity is critical for NF-κB-dependent survival and proliferation of malignant cancer cells, which is fostered by paracaspase-catalyzed inactivation of negative regulators of the canonical NF-κB pathway like A20, CYLD and RelB. Specifically, B cell receptor-addicted lymphomas rely strongly on this cancer cell-intrinsic MALT1 protease function, but also survival, proliferation and metastasis of certain solid cancers is sensitive to MALT1 inhibition. Beyond this, MALT1 protease exercises a cancer cell-extrinsic role by maintaining the immune-suppressive function of regulatory T (Treg) cells in the tumor microenvironment (TME). MALT1 inhibition is able to convert immune-suppressive to pro-inflammatory Treg cells in the TME of solid cancers, thereby eliciting a robust anti-tumor immunity that can augment the effects of checkpoint inhibitors. Therefore, the cancer cell-intrinsic and -extrinsic tumor promoting MALT1 protease functions offer unique therapeutic opportunities, which has motivated the development of potent and selective MALT1 inhibitors currently under pre-clinical and clinical evaluation.
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Affiliation(s)
- Thomas J O'Neill
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Marie J Tofaute
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Daniel Krappmann
- Research Unit Signaling and Translation, Group Signaling and Immunity, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
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15
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Jiang VC, Liu Y, Lian J, Huang S, Jordan A, Cai Q, Lin R, Yan F, McIntosh J, Li Y, Che Y, Chen Z, Vargas J, Badillo M, Bigcal JN, Lee HH, Wang W, Yao Y, Nie L, Flowers CR, Wang M. Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma. J Clin Invest 2023; 133:e165694. [PMID: 36719376 PMCID: PMC9888382 DOI: 10.1172/jci165694] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/07/2022] [Indexed: 02/01/2023] Open
Abstract
Bruton's tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11-knockout cells showed antitumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK/CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K/AKT/mTOR, and integrin signaling. Importantly, cotargeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.
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Affiliation(s)
| | - Yang Liu
- Department of Lymphoma and Myeloma and
| | | | | | | | | | - Ruitao Lin
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Fangfang Yan
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | | | - Yijing Li
- Department of Lymphoma and Myeloma and
| | | | | | | | | | | | | | - Wei Wang
- Department of Lymphoma and Myeloma and
| | - Yixin Yao
- Department of Lymphoma and Myeloma and
| | - Lei Nie
- Department of Lymphoma and Myeloma and
| | | | - Michael Wang
- Department of Lymphoma and Myeloma and
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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16
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Peng ZM, Zhang YY, Wei D, Zhang XJ, Liu B, Peng J, Luo XJ. MALT1 promotes necroptosis in stroke rat brain via targeting the A20/RIPK3 pathway. Arch Biochem Biophys 2023; 735:109502. [PMID: 36603698 DOI: 10.1016/j.abb.2023.109502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/30/2022] [Accepted: 01/01/2023] [Indexed: 01/04/2023]
Abstract
Necroptosis has been demonstrated to contribute to brain injury in ischemic stroke, whereas A20 can exert anti-necroptosis effect via deubiquitinating receptor-interacting protein kinase (RIPK3) at k63 and it can be cleaved by MALT1. This study aims to explore whether MALT1 is upregulated in the brain during ischemic stroke and promotes brain cell necroptosis through enhancing the degradation of A20. Ischemic stroke model was established in Sprague Dawley rats by occlusion of the middle cerebral artery (MCA) for 2 h, followed by 24 h reperfusion, which showed brain injury (increase in neurological deficit score and infarct volume) concomitant with an upregulation of MALT1, a decrease in A20 level, and increases in necroptosis-associated protein levels [RIPK3, mixed lineage kinase domain-like protein (MLKL) and p-MLKL] and k63-ubiquitination of RIPK3 in brain tissues. Administration of MALT1 inhibitor (Ml-2) at 8 or 15 mg/kg (i.p.) at 1 h after ischemia significantly improved neurological function and reduced infarct volume together with a downregulation of MALT1, an increase in A20 level and decreases in necroptosis-associated protein levels and k63-ubiquitination of RIPK3. Similarly, knockdown of MALT1 could also reduce oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in the cultured HT22 cells coincident with an increase in A20 level and decreases in necroptosis-associated protein levels and k63-ubiquitination of RIPK3. Based on these observations, we conclude that MALT1 promotes necroptosis in stroke rat brain via enhancing the degradation of A20, which leads to a decrease in the capability of A20 to deubiquitinate RIPK3 at k63 and a subsequent compromise in counteraction against the brain cell necroptosis.
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Affiliation(s)
- Zi-Mei Peng
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China; Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Yi-Yue Zhang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Dan Wei
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Xiao-Jie Zhang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Pharmacy, Xiangya Hospital, Central South University, Hunan, China
| | - Bin Liu
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Jun Peng
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Pharmacy, Xiangya Hospital, Central South University, Hunan, China
| | - Xiu-Ju Luo
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
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17
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Mempel TR, Krappmann D. Combining precision oncology and immunotherapy by targeting the MALT1 protease. J Immunother Cancer 2022; 10:e005442. [PMID: 36270731 PMCID: PMC9594517 DOI: 10.1136/jitc-2022-005442] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2022] [Indexed: 11/30/2022] Open
Abstract
An innovative strategy for cancer therapy is to combine the inhibition of cancer cell-intrinsic oncogenic signaling with cancer cell-extrinsic immunological activation of the tumor microenvironment (TME). In general, such approaches will focus on two or more distinct molecular targets in the malignant cells and in cells of the surrounding TME. In contrast, the protease Mucosa-associated lymphoid tissue protein 1 (MALT1) represents a candidate to enable such a dual approach by engaging only a single target. Originally identified and now in clinical trials as a lymphoma drug target based on its role in the survival and proliferation of malignant lymphomas addicted to chronic B cell receptor signaling, MALT1 proteolytic activity has recently gained additional attention through reports describing its tumor-promoting roles in several types of non-hematological solid cancer, such as breast cancer and glioblastoma. Besides cancer cells, regulatory T (Treg) cells in the TME are particularly dependent on MALT1 to sustain their immune-suppressive functions, and MALT1 inhibition can selectively reprogram tumor-infiltrating Treg cells into Foxp3-expressing proinflammatory antitumor effector cells. Thereby, MALT1 inhibition induces local inflammation in the TME and synergizes with anti-PD-1 checkpoint blockade to induce antitumor immunity and facilitate tumor control or rejection. This new concept of boosting tumor immunotherapy in solid cancer by MALT1 precision targeting in the TME has now entered clinical evaluation. The dual effects of MALT1 inhibitors on cancer cells and immune cells therefore offer a unique opportunity for combining precision oncology and immunotherapy to simultaneously impair cancer cell growth and neutralize immunosuppression in the TME. Further, MALT1 targeting may provide a proof of concept that modulation of Treg cell function in the TME represents a feasible strategy to augment the efficacy of cancer immunotherapy. Here, we review the role of MALT1 protease in physiological and oncogenic signaling, summarize the landscape of tumor indications for which MALT1 is emerging as a therapeutic target, and consider strategies to increase the chances for safe and successful use of MALT1 inhibitors in cancer therapy.
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Affiliation(s)
- Thorsten R Mempel
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel Krappmann
- Research Unit Cellular Signal Integration, Molecular Targets and Therapeutics Center, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany
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18
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Haselager MV, Eldering E. The Therapeutic Potential of Targeting NIK in B Cell Malignancies. Front Immunol 2022; 13:930986. [PMID: 35911754 PMCID: PMC9326486 DOI: 10.3389/fimmu.2022.930986] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/08/2022] [Indexed: 11/24/2022] Open
Abstract
NF-κB-inducing kinase (NIK) is a key player in non-canonical NF-κB signaling, involved in several fundamental cellular processes, and is crucial for B cell function and development. In response to certain signals and ligands, such as CD40, BAFF and lymphotoxin-β activation, NIK protein stabilization and subsequent NF-κB activation is achieved. Overexpression or overactivation of NIK is associated with several malignancies, including activating mutations in multiple myeloma (MM) and gain-of-function in MALT lymphoma as a result of post-translational modifications. Consequently, drug discovery studies are devoted to pharmacologic modulation of NIK and development of specific novel small molecule inhibitors. However, disease-specific in vitro and in vivo studies investigating NIK inhibition are as of yet lacking, and clinical trials with NIK inhibitors remain to be initiated. In order to bridge the gap between bench and bedside, this review first briefly summarizes our current knowledge on NIK activation, functional activity and stability. Secondly, we compare current inhibitors targeting NIK based on efficacy and specificity, and provide a future perspective on the therapeutic potential of NIK inhibition in B cell malignancies.
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Affiliation(s)
- Marco V. Haselager
- Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam, Netherlands
- Lymphoma and Myeloma Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam, Netherlands
- Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, Netherlands
| | - Eric Eldering
- Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam, Netherlands
- Lymphoma and Myeloma Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam, Netherlands
- Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, Netherlands
- *Correspondence: Eric Eldering,
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19
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Zhang YY, Peng J, Luo XJ. Post-translational modification of MALT1 and its role in B cell- and T cell-related diseases. Biochem Pharmacol 2022; 198:114977. [PMID: 35218741 DOI: 10.1016/j.bcp.2022.114977] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/18/2022] [Accepted: 02/18/2022] [Indexed: 02/06/2023]
Abstract
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a multifunctional protein. MALT1 functions as an adaptor protein to assemble and recruit proteins such as B-cell lymphoma 10 (BCL10) and caspase-recruitment domain (CARD)-containing coiled-coil protein 11 (CARD11). Conversely it also acts as a paracaspase to cleave specified substrates. Because of its involvement in immunity, inflammation and cancer through its dual functions of scaffolding and catalytic activity, MALT1 is becoming a promising therapeutic target in B cell- and T cell-related diseases. There is growing evidence that the function of MALT1 is subtly modulated via post-translational modifications. This review summarized recent progress in relevant studies regarding the physiological and pathophysiological functions of MALT1, post-translational modifications of MALT1 and its role in B cell- and T cell- related diseases. In addition, the current available MALT1 inhibitors were also discussed.
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Affiliation(s)
- Yi-Yue Zhang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Jun Peng
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
| | - Xiu-Ju Luo
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha 410013, China.
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20
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Chen R, Zhou D, Wang L, Zhu L, Ye X. MYD88L265P and CD79B double mutations type (MCD type) of diffuse large B-cell lymphoma: mechanism, clinical characteristics, and targeted therapy. Ther Adv Hematol 2022; 13:20406207211072839. [PMID: 35126963 PMCID: PMC8808040 DOI: 10.1177/20406207211072839] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/15/2021] [Indexed: 12/15/2022] Open
Abstract
MYD88/CD79B-mutated (MCD) genotype is a genetic subgroup of diffuse large B-cell lymphoma (DLBCL) with the co-occurrence of MYD88L265P and CD79B mutations. MCD genotype is characterized by poor prognosis and extranodal involvement especially in immune-privileged sites. MCD model is dominated by activated B-cell (ABC)-like subtype of DLBCLs. It is generally accepted that the pathogenesis of MCD DLBCL mainly includes chronic active B-cell receptor (BCR) signaling and oncogenic MYD88 mutations, which drives pathological nuclear factor kappa B (NF-κB) activation in MCD lymphoid malignancies. CD79B and MYD88L265P mutations are frequently and contemporaneously founded in B-cell malignancies. The collaboration of the two mutations may explain the unique biology of MCD. Meanwhile, standard immunochemotherapy combine with different targeted therapies worth further study to improve the prognosis of MCD, according to genetic, phenotypic, and clinical features of MCD type. In this review, we systematically described mechanism, clinical characteristics, and targeted therapy of MCD DLBCL.
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Affiliation(s)
- Rongrong Chen
- Program in Clinical Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - De Zhou
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lulu Wang
- Program in Clinical Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lixia Zhu
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiujin Ye
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China
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21
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Recent Advances in the Genetic of MALT Lymphomas. Cancers (Basel) 2021; 14:cancers14010176. [PMID: 35008340 PMCID: PMC8750177 DOI: 10.3390/cancers14010176] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of marginal zone lymphomas. These B-cell neoplasms may arise from many organs and usually have an indolent behavior. Recurrent chromosomal translocations and cytogenetic alterations are well characterized, some of them being associated to specific sites. Through next-generation sequencing technologies, the mutational landscape of MALT lymphomas has been explored and available data to date show that there are considerable variations in the incidence and spectrum of mutations among MALT lymphoma of different sites. Interestingly, most of these mutations affect several common pathways and some of them are potentially targetable. Gene expression profile and epigenetic studies have also added new information, potentially useful for diagnosis and treatment. This article provides a comprehensive review of the genetic landscape in MALT lymphomas. Abstract Mucosa-associated lymphoid tissue (MALT) lymphomas are a diverse group of lymphoid neoplasms with B-cell origin, occurring in adult patients and usually having an indolent clinical behavior. These lymphomas may arise in different anatomic locations, sharing many clinicopathological characteristics, but also having substantial variances in the aetiology and genetic alterations. Chromosomal translocations are recurrent in MALT lymphomas with different prevalence among different sites, being the 4 most common: t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). Several chromosomal numerical abnormalities have also been described, but probably represent secondary genetic events. The mutational landscape of MALT lymphomas is wide, and the most frequent mutations are: TNFAIP3, CREBBP, KMT2C, TET2, SPEN, KMT2D, LRP1B, PRDM1, EP300, TNFRSF14, NOTCH1/NOTCH2, and B2M, but many other genes may be involved. Similar to chromosomal translocations, certain mutations are enriched in specific lymphoma types. In the same line, variation in immunoglobulin gene usage is recognized among MALT lymphoma of different anatomic locations. In the last decade, several studies have analyzed the role of microRNA, transcriptomics and epigenetic alterations, further improving our knowledge about the pathogenic mechanisms in MALT lymphoma development. All these advances open the possibility of targeted directed treatment and push forward the concept of precision medicine in MALT lymphomas.
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22
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Abstract
The activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) has an aggressive course and is associated with poor prognosis in the relapsed or refractory setting. ABC-DLBCL is characterized by chronic active signaling of NF-κB, which is dependent on the CARD11-BCL10-MALT1 (CBM) complex. MALT1 is a key effector of the CBM complex and activates canonical NF-κB and AP-1 among other transcription factors via distinct protease and scaffold functions. There is therefore growing interest in therapeutic targeting of MALT1 for B-cell malignancies. Here, we review recent advances in therapeutic targeting of MALT1 for ABC-DLBCL. Covalent and allosteric MALT1 protease inhibitors have been developed which inhibit growth of ABC-DLBCL in preclinical models, and two clinical MALT1 protease inhibitors are being developed in phase I clinical trials. Importantly, these compounds can overcome resistance to BTK inhibitors in preclinical models. Alternative compounds blocking the scaffold effect of MALT1 are also in early preclinical development. Blockade of MALT1 protease activity may have important implications for anti-lymphoma immunity by increasing immunogenicity of ABC-DLBCL cells and also by potentiating anti-lymphoma activity of other immune cells in the lymphoma microenvironment. Together, early data suggest that MALT1 is a promising target for ABC-DLBCL and possibly other B-cell malignancies, and can have lymphoma cell-intrinsic as well as immune-mediated therapeutic effects.
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Affiliation(s)
- Madhav R Seshadri
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Ari M Melnick
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, Cornell University, New York, NY, USA
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23
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Hamp I, O'Neill TJ, Plettenburg O, Krappmann D. A patent review of MALT1 inhibitors (2013-present). Expert Opin Ther Pat 2021; 31:1079-1096. [PMID: 34214002 DOI: 10.1080/13543776.2021.1951703] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION MALT1 is the only human paracaspase, a protease with unique cleavage activity and substrate specificity. As a key regulator of immune responses, MALT1 has attracted attention as an immune modulatory target for the treatment of autoimmune/inflammatory diseases. Further, chronic MALT1 protease activation drives survival of lymphomas, suggesting that MALT1 is a suitable drug target for lymphoid malignancies. Recent studies have indicated that MALT1 inhibition impairs immune suppressive function of regulatory T cells in the tumor microenvironment, suggesting that MALT1 inhibitors may boost anti-tumor immunity in the treatment of solid cancers. AREAS COVERED This review summarizes the literature on MALT1 patents and applications. We discuss the potential therapeutic uses for MALT1 inhibitors based on patents and scientific literature. EXPERT OPINION There has been a steep increase in MALT1 inhibitor patents. Compounds with high selectivity and good bioavailability have been developed. An allosteric binding pocket is the preferred site for potent and selective MALT1 targeting. MALT1 inhibitors have moved to early clinical trials, but toxicological studies indicate that long-term MALT1 inhibition can disrupt immune homeostasis and lead to autoimmunity. Even though this poses risks, preventing immune suppression may favor the use of MALT1 inhibitors in cancer immunotherapies.
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Affiliation(s)
- Isabel Hamp
- Institute for Medicinal Chemistry, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.,Centre of Biomolecular Drug Research (BMWZ), Institute of Organic Chemistry, Leibniz Universität Hannover, Hannover, Germany
| | - Thomas J O'Neill
- Research Unit Cellular Signal Integration, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Oliver Plettenburg
- Institute for Medicinal Chemistry, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.,Centre of Biomolecular Drug Research (BMWZ), Institute of Organic Chemistry, Leibniz Universität Hannover, Hannover, Germany
| | - Daniel Krappmann
- Research Unit Cellular Signal Integration, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
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24
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Liang X, Sun C, Li C, Yu H, Wei X, Liu X, Bao W, Shi Y, Sun X, Khamrakulov M, Yang C, Liu H. Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma. J Med Chem 2021; 64:9217-9237. [PMID: 34181850 DOI: 10.1021/acs.jmedchem.1c00466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.
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Affiliation(s)
- Xuewu Liang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chenxia Sun
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200043, China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
| | - Chunpu Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Haolan Yu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200043, China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
| | - Xiaohui Wei
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuyi Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wei Bao
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200043, China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
| | - Yuqiang Shi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaochen Sun
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200043, China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
| | - Mirzadavlat Khamrakulov
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chenghua Yang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200043, China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
| | - Hong Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China.,School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
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Kiesewetter B, Copie-Bergman C, Levy M, Wu F, Dupuis J, Barau C, Arcaini L, Paulli M, Lucioni M, Bonometti A, Salar A, Fernández-Rodriguez C, Piris MA, Cucco F, Dobson R, Li Y, Chen Z, Robe C, Simonitsch-Klupp I, Wotherspoon A, Raderer M, Du MQ. Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. Cancers (Basel) 2021; 13:2993. [PMID: 34203889 PMCID: PMC8232676 DOI: 10.3390/cancers13122993] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/07/2021] [Accepted: 06/10/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND In Western countries, the prevalence of gastric mucosa-associated lymphoid tissue (MALT) lymphoma has declined over the last three decades. Contemporaneously, H. pylori negative gastric MALT lymphoma is increasingly encountered, and their genetic basis and clinical features remain elusive. METHODS A total of 57 cases of H. pylori negative gastric MALT lymphoma were reviewed and investigated for chromosome translocation by fluorescence in-situ hybridization and for somatic mutations by the targeted sequencing of 93 genes. RESULTS MALT1 translocation, most likely t(11;18)(q21;q21)/BIRC3-MALT1, was detected in 39% (22/57) cases, and IGH translocation was further seen in 12 MALT1-negative cases, together accounting for 60% of the cohort. Targeted sequencing was successful in 35 cases, and showed frequent mutations in NF-κB signaling pathways (TNFAIP3 = 23%, CARD11 = 9%, MAP3K14 = 9%), together affecting 14 cases (40%). The NF-κB pathway mutations were mutually exclusive from MALT1, albeit not IGH translocation, altogether occurring in 86% of cases. There was no significant correlation between the genetic changes and clinicopathological parameters. The patients showed a median of progression-free survival (PFS) of 66.3 months, and a significant superior PFS when treated with systemic versus antibiotic therapy (p = 0.004). CONCLUSION H. pylori negative gastric MALT lymphoma is characterized by highly frequent genetic changes in the NF-κB signaling pathways.
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Affiliation(s)
- Barbara Kiesewetter
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge CB2 1TN, UK; (F.W.); (F.C.); (R.D.); (Y.L.); (Z.C.)
- Department of Medicine I, Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Christiane Copie-Bergman
- Groupe Henri Mondor-Albert Chenevier, Département de Pathologie, APHP, INSERM U955, Université Paris Est, 94010 Créteil, France; (C.C.-B.); (C.R.)
| | - Michael Levy
- Groupe Henri Mondor-Albert Chenevier and EC2M3 EA7375 Research Unit, Department of Gastroenterology, APHP, 94010 Créteil, France;
| | - Fangtian Wu
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge CB2 1TN, UK; (F.W.); (F.C.); (R.D.); (Y.L.); (Z.C.)
- Department of Hematology, Pukou CLL Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jehan Dupuis
- Lymphoid Malignancies Unit, APHP, Groupe Hospitalier Henri Mondor-Albert Chenevier, 94010 Créteil, France;
| | - Caroline Barau
- Plateforme de Ressources Biologiques BB-0033-00021, APHP, Groupe Hospitalier Henri Mondor-Albert Chenevier, 94010 Créteil, France;
| | - Luca Arcaini
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Marco Paulli
- Department of Pathology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.P.); (M.L.)
| | - Marco Lucioni
- Department of Pathology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.P.); (M.L.)
| | - Arturo Bonometti
- Anatomic Pathology, Department of Molecular Medicine University of Pavia & Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Antonio Salar
- Department of Hematology, Hospital del Mar & Instituto de investigaciones médicas Hospital del Mar (IMIM), 08003 Barcelona, Spain;
| | | | - Miguel A. Piris
- Pathology Department, Hospital Fundación Jiménez Díaz, 28040 Madrid, Spain;
| | - Francesco Cucco
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge CB2 1TN, UK; (F.W.); (F.C.); (R.D.); (Y.L.); (Z.C.)
| | - Rachel Dobson
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge CB2 1TN, UK; (F.W.); (F.C.); (R.D.); (Y.L.); (Z.C.)
| | - Yan Li
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge CB2 1TN, UK; (F.W.); (F.C.); (R.D.); (Y.L.); (Z.C.)
- Department of Haematology, Hebei General Hospital, Shijiazhuang 050000, China
| | - Zi Chen
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge CB2 1TN, UK; (F.W.); (F.C.); (R.D.); (Y.L.); (Z.C.)
| | - Cyrielle Robe
- Groupe Henri Mondor-Albert Chenevier, Département de Pathologie, APHP, INSERM U955, Université Paris Est, 94010 Créteil, France; (C.C.-B.); (C.R.)
| | | | - Andrew Wotherspoon
- Department of Histopathology, The Royal Marsden Hospital, 203 Fulham Rd, London SW3 6JJ, UK;
| | - Markus Raderer
- Department of Medicine I, Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Ming Qing Du
- Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge CB2 1TN, UK; (F.W.); (F.C.); (R.D.); (Y.L.); (Z.C.)
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26
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Liang X, Cao Y, Li C, Yu H, Yang C, Liu H. MALT1 as a promising target to treat lymphoma and other diseases related to MALT1 anomalies. Med Res Rev 2021; 41:2388-2422. [PMID: 33763890 DOI: 10.1002/med.21799] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 12/23/2020] [Accepted: 03/03/2021] [Indexed: 12/25/2022]
Abstract
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key adaptor protein that regulates the NF-κB pathway, in which MALT1 functions as a scaffold protein and protease to trigger downstream signals. The abnormal expression of MALT1 is closely associated with lymphomagenesis and other diseases, including solid tumors and autoimmune diseases. MALT1 is the only protease in the underlying pathogenesis of these diseases, and its proteolytic activity can be pharmacologically regulated. Therefore, MALT1 is a potential and promising target for anti-lymphoma and other MALT1-related disease treatments. Currently, the development of MALT1 inhibitors is still in its early stages. This review presents an overview of MALT1, particularly its X-ray structures and biological functions, and elaborates on the pathogenesis of diseases associated with its dysregulation. We then summarize previously reported MALT1 inhibitors, focusing on their molecular structure, biological activity, structure-activity relationship, and limitations. Finally, we propose future research directions to accelerate the discovery of novel MALT1 inhibitors with clinical applications. Overall, this review provides a comprehensive and systematic overview of MALT1-related research advances and serves as a theoretical basis for drug discovery and research.
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Affiliation(s)
- Xuewu Liang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - YiChun Cao
- School of Pharmacy, Fudan University, Shanghai, China
| | - Chunpu Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Haolan Yu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Chenghua Yang
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hong Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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27
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Lu HY, Turvey SE. Human MALT1 deficiency and predisposition to infections. Curr Opin Immunol 2021; 72:1-12. [PMID: 33714841 DOI: 10.1016/j.coi.2021.02.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/18/2021] [Accepted: 02/26/2021] [Indexed: 12/20/2022]
Abstract
Human germline MALT1 deficiency is an inborn error of immunity characterized by recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. The number of identified MALT1-deficient patients have greatly increased in the past two years, which has significantly improved our understanding of the clinical features of this disorder. Patients frequently experience infections affecting the respiratory, skin, gastrointestinal, and blood systems. The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus. Enhanced susceptibility to S. aureus and C. albicans is likely due to impaired Th17 immunity, similar to STAT3 and IL-17 pathway deficiencies.
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Affiliation(s)
- Henry Y Lu
- Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada
| | - Stuart E Turvey
- Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.
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28
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Morgan D, Garg M, Tergaonkar V, Tan SY, Sethi G. Pharmacological significance of the non-canonical NF-κB pathway in tumorigenesis. Biochim Biophys Acta Rev Cancer 2020; 1874:188449. [PMID: 33058996 DOI: 10.1016/j.bbcan.2020.188449] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/04/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023]
Abstract
The understanding of the impact of the non-canonical NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway in several human diseases including autoimmune, inflammatory and cancers has been on the rise. This pathway induces the expression of several important genes involved in diverse biological processes. Though progress has been made in understanding the activation, regulation and biological functions of the non-canonical NF-κB signaling mechanism, no specific drug has been approved to target NF-κB inducing kinase (NIK), the key signaling molecule in this pathway. The inhibition of NIK can serve as a potential therapeutic strategy for various ailments, especially for the treatment of different types of human cancers. There are other targetable downstream molecules in this pathway as well. This review highlights the possible role of the non-canonical NF-κB pathway in normal physiology as well as in different cancers and discusses about various pharmacological strategies to modulate the activation of this pathway.
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Affiliation(s)
- Dhakshayini Morgan
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Uttar Pradesh, Noida 201313, India
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
| | - Soo Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore; Advanced Molecular Pathology Laboratory, Institute of Molecular and Cell Biology, 61 Biopolis Dr, 138673, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 600, Singapore.
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29
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Cheng J, Klei LR, Hubel NE, Zhang M, Schairer R, Maurer LM, Klei HB, Kang H, Concel VJ, Delekta PC, Dang EV, Mintz MA, Baens M, Cyster JG, Parameswaran N, Thome M, Lucas PC, McAllister-Lucas LM. GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein. J Clin Invest 2020; 130:1036-1051. [PMID: 31961340 DOI: 10.1172/jci97040] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 11/06/2019] [Indexed: 12/11/2022] Open
Abstract
Antigen receptor-dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein-coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.
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Affiliation(s)
| | | | - Nathaniel E Hubel
- Department of Pediatrics and.,Department of Pathology, University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Ming Zhang
- Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland
| | - Rebekka Schairer
- Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland
| | | | | | - Heejae Kang
- Department of Pathology, University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | | | - Phillip C Delekta
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA
| | - Eric V Dang
- Department of Biophysics and Biochemistry, UCSF, San Francisco, California, USA
| | - Michelle A Mintz
- Department of Biophysics and Biochemistry, UCSF, San Francisco, California, USA
| | - Mathijs Baens
- Human Genome Laboratory, VIB Center for the Biology of Disease, and.,Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Jason G Cyster
- Department of Biophysics and Biochemistry, UCSF, San Francisco, California, USA.,Howard Hughes Medical Institute and.,Department of Microbiology and Immunology, UCSF, San Francisco, California, USA
| | | | - Margot Thome
- Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland
| | - Peter C Lucas
- Department of Pathology, University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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30
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Lue JK, O’Connor OA, Bertoni F. Targeting pathogenic mechanisms in marginal zone lymphoma: from concepts and beyond. ANNALS OF LYMPHOMA 2020; 4:7. [PMID: 34667996 PMCID: PMC7611845 DOI: 10.21037/aol-20-20] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Marginal zone lymphoma (MZL) represents a group of three distinct though overlapping lymphoid malignancies that includes extranodal, nodal and splenic marginal lymphoma. MZL patients usually present an indolent clinical course, although the disease remains largely incurable, save early stage disease that might be irradiated. Therapeutic advances have been limited due to the small patient population, and have largely been adapted from other indolent lymphomas. Here, we discuss the numerous targets and pathways which may offer the prospect of directly inhibiting the mechanisms identified promoting and sustaining marginal zone lymphomagenesis. In particular, we focus on the agents that may have at least a theoretical application in the disease. Various dysregulated pathways converge to produce an overarching stimulation of nuclear factor κB (NF-κB) and the MYD88-IRAK4 axis, which can be thus leveraged or targeting B-cell receptor signaling through BTK inhibitors (such as ibrutinib, zanubrutinib, acalabrutinib) and PI3K inhibitors (such as idelalisib, copanlisib, duvelisib umbralisib) or via more novel agents in development such as MALT1 inhibitors, SMAC mimetics, NIK inhibitors, IRAK4 or MYD88 inhibitors. NOTCH signaling is also crucial for marginal zone cells, but no clinical data are available with NOTCH inhibitors such as the γ-secretase inhibitor PF-03084014 or the NICD inhibitor CB-103. The hypermethylation phenotype, the overexpression of the PRC2-complex or the presence of TET2 mutations reported in MZL subsets make epigenetic agents (demethylating agents, EZH2 inhibitors, HDAC inhibitors) also potential therapeutic tools for MZL patients.
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Affiliation(s)
- Jennifer K. Lue
- Division of Hematology-Oncology, Department of Medicine, Columbia University Medical Center, Center for Lymphoid Malignancies, New York, NY, USA
| | - Owen A. O’Connor
- Division of Hematology and Oncology, Program for T-Cell Lymphoma Research, University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Francesco Bertoni
- institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland
- Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
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31
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32
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Kumar S, Fairmichael C, Longley DB, Turkington RC. The Multiple Roles of the IAP Super-family in cancer. Pharmacol Ther 2020; 214:107610. [PMID: 32585232 DOI: 10.1016/j.pharmthera.2020.107610] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/16/2020] [Accepted: 06/08/2020] [Indexed: 12/22/2022]
Abstract
The Inhibitor of Apoptosis proteins (IAPs) are a family of proteins that are mainly known for their anti-apoptotic activity and ability to directly bind and inhibit caspases. Recent research has however revealed that they have extensive roles in governing numerous other cellular processes. IAPs are known to modulate ubiquitin (Ub)-dependent signaling pathways through their E3 ligase activity and influence activation of nuclear factor κB (NF-κB). In this review, we discuss the involvement of IAPs in individual hallmarks of cancer and the current status of therapies targeting these critical proteins.
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Affiliation(s)
- Swati Kumar
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Ciaran Fairmichael
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Daniel B Longley
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Richard C Turkington
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom.
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33
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Izumi K, Nishikori M, Yuan H, Otsuka Y, Nakao K, Takaori-Kondo A. Establishment and characterization of a MALT lymphoma cell line carrying an API2-MALT1 translocation. Genes Chromosomes Cancer 2020; 59:517-524. [PMID: 32348592 DOI: 10.1002/gcc.22855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 04/21/2020] [Accepted: 04/23/2020] [Indexed: 11/07/2022] Open
Abstract
MALT lymphomas with API2(BIRC3)-MALT1 translocation usually have an indolent clinical course and rarely transform into aggressive lymphoma, and there have been no lymphoma cell lines carrying API2-MALT1 translocation reported to date. We established a novel lymphoma cell line named BMA19, carrying the API2-MALT1 translocation from a patient with histologic transformation of intestinal MALT lymphoma. The cells were suggested to carry API2-MALT1 and MYC-IGH translocations by chromosomal analysis, and these translocations were confirmed by polymerase chain reaction analysis. The expression of MYC was shown to be enhanced as a result of the MYC-IGH translocation, and it is considered to have played a role in the histologic transformation of MALT lymphoma. Whole exome sequencing of BMA19 identified several nucleotide variations in genes reported to be mutated in previous studies of marginal zone lymphomas. The MALT1 inhibitor MI-2 specifically decreased cell growth, and the BMA19 cell line was suggested to be still dependent on the API2-MALT1 signal. Subtractive microarray analysis showed that one of the earliest events resulting from MALT1 inhibition is increased susceptibility to endoplasmic reticulum stress-induced apoptosis. The BMA19 cell line is considered to conserve the biological properties of MALT lymphoma and is expected to be a valuable tool for research into the pathogenesis of MALT lymphoma with an API2-MALT1 translocation.
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Affiliation(s)
- Kiyotaka Izumi
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Momoko Nishikori
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hepei Yuan
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yasuyuki Otsuka
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kensuke Nakao
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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34
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Xu X, Kalac M, Markson M, Chan M, Brody JD, Bhagat G, Ang RL, Legarda D, Justus SJ, Liu F, Li Q, Xiong H, Ting AT. Reversal of CYLD phosphorylation as a novel therapeutic approach for adult T-cell leukemia/lymphoma (ATLL). Cell Death Dis 2020; 11:94. [PMID: 32024820 PMCID: PMC7002447 DOI: 10.1038/s41419-020-2294-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 01/21/2020] [Accepted: 01/22/2020] [Indexed: 11/08/2022]
Abstract
Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of mature T cells associated with chronic infection by human T-cell lymphotropic virus type-1 (HTLV-1). ATLL patients with aggressive subtypes have dismal outcomes. We demonstrate that ATLL cells co-opt an early checkpoint within the tumor necrosis factor receptor 1 (TNFR1) pathway, resulting in survival advantage. This early checkpoint revolves around an interaction between the deubiquitinase CYLD and its target RIPK1. The status of RIPK1 K63-ubiquitination determines cell fate by creating either a prosurvival signal (ubiquitinated RIPK1) or a death signal (deubiquitinated RIPK1). In primary ATLL samples and in cell line models, an increased baseline level of CYLD phosphorylation was observed. We therefore tested the hypothesis that this modification of CYLD, which has been reported to inhibit its deubiquitinating function, leads to increased RIPK1 ubiquitination and thus provides a prosurvival signal to ATLL cells. CYLD phosphorylation can be pharmacologically reversed by IKK inhibitors, specifically by TBK1/IKKε and IKKβ inhibitors (MRT67307 and TPCA). Both of the IKK sub-families can phosphorylate CYLD, and the combination of MRT67307 and TPCA have a marked effect in reducing CYLD phosphorylation and triggering cell death. ATLL cells overexpressing a kinase-inactive TBK1 (TBK1-K38A) demonstrate lower CYLD phosphorylation and subsequently reduced proliferation. IKK blockade reactivates CYLD, as evidenced by the reduction in RIPK1 ubiquitination, which leads to the association of RIPK1 with the death-inducing signaling complex (DISC) to trigger cell death. In the absence of CYLD, RIPK1 ubiquitination remains elevated following IKK blockade and it does not associate with the DISC. SMAC mimetics can similarly disrupt CYLD phosphorylation and lead to ATLL cell death through reduction of RIPK1 ubiquitination, which is CYLD dependent. These results identify CYLD as a crucial regulator of ATLL survival and point to its role as a potential novel target for pharmacologic modification in this disease.
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Affiliation(s)
- Xin Xu
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Geriatrics, Hematology & Oncology Ward, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, GuangDong, 510180, People's Republic of China
| | - Matko Kalac
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Michael Markson
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Mark Chan
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Joshua D Brody
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, 10032, USA
| | - Rosalind L Ang
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Diana Legarda
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Scott J Justus
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Feng Liu
- Department of Geriatrics, Hematology & Oncology Ward, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, GuangDong, 510180, People's Republic of China
| | - Qingshan Li
- Department of Hematology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, GuangDong, 510180, People's Republic of China
| | - Huabao Xiong
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Adrian T Ting
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA.
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35
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Zhu L, Tang F, Lei Z, Guo C, Song Y, Huang J, Xia X. Antiapoptotic properties of MALT1 protease are associated with redox homeostasis in ABC-DLBCL cells. Mol Carcinog 2019; 58:2340-2352. [PMID: 31556968 DOI: 10.1002/mc.23122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 09/03/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023]
Abstract
Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) protease presents crucial antiapoptotic properties in activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL); however, the mechanism is unclear. Here, we reported that inhibition of MALT1 protease in ABC-DLBCL cells led to cell apoptosis, along with elevated mitochondrial reactive oxygen species production and a reduced oxygen consumption rate. These alterations induced by MALT1 protease inhibition were associated with reduced expression of glutaminase (GLS1) and glutathione levels. We further show that MALT1 protease was required for the activation and nuclear translocation of c-Jun, which functions as a transcription factor of the GLS1 gene by binding directly to its promoter region. Taken together, MALT1 protease maintained mitochondrial redox homeostasis and mitochondrial bioenergetics through the MALT1-c-Jun-GLS1-coupled metabolic pathway to defend against apoptosis in ABC-DLBCL cells, which raises exciting possibilities regarding targeting of the MALT1-c-Jun-GLS1 axis as a potential therapeutic strategy against ABC-DLBCL.
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Affiliation(s)
- Leqing Zhu
- The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou, China
| | - Fen Tang
- The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou, China
| | - Zhiwei Lei
- The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou, China.,Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China
| | - Chengbin Guo
- The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou, China
| | - Yueqi Song
- The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou, China
| | - Junqing Huang
- Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Xichun Xia
- The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou, China
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36
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Liu Z, Mar KB, Hanners NW, Perelman SS, Kanchwala M, Xing C, Schoggins JW, Alto NM. A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB. Nature 2019; 568:249-253. [PMID: 30894749 PMCID: PMC6812682 DOI: 10.1038/s41586-019-1041-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 02/18/2019] [Indexed: 12/31/2022]
Abstract
The non-canonical NF-κB signalling cascade is essential for lymphoid organogenesis, B cell maturation, osteoclast differentiation, and inflammation in mammals1,2; dysfunction of this system is associated with human diseases, including immunological disorders and cancer3-6. Although expression of NF-κB-inducing kinase (NIK, also known as MAP3K14) is the rate-limiting step in non-canonical NF-κB pathway activation2,7, the mechanisms by which transcriptional responses are regulated remain largely unknown. Here we show that the sine oculis homeobox (SIX) homologue family transcription factors SIX1 and SIX2 are integral components of the non-canonical NF-κB signalling cascade. The developmentally silenced SIX proteins are reactivated in differentiated macrophages by NIK-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 target a subset of inflammatory gene promoters and directly inhibit the trans-activation function of the transcription factors RELA and RELB in a negative feedback circuit. In support of a physiologically pivotal role for SIX proteins in host immunity, a human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS/P53-driven non-small-cell lung carcinomas from inflammatory cell death induced by SMAC-mimetic chemotherapeutic agents (small-molecule activators of the non-canonical NF-κB pathway). Our findings identify a NIK-SIX signalling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.
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Affiliation(s)
- Zixu Liu
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Katrina B Mar
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Natasha W Hanners
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Sofya S Perelman
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Mohammed Kanchwala
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Chao Xing
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - John W Schoggins
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Neal M Alto
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Mucosa-associated lymphoid tissue lymphoma with t(11;18)(q21;q21) translocation: long-term follow-up results. Ann Hematol 2019; 98:1675-1687. [DOI: 10.1007/s00277-019-03671-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 03/17/2019] [Indexed: 12/16/2022]
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38
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Gehlhausen JR, Hawley E, Wahle BM, He Y, Edwards D, Rhodes SD, Lajiness JD, Staser K, Chen S, Yang X, Yuan J, Li X, Jiang L, Smith A, Bessler W, Sandusky G, Stemmer-Rachamimov A, Stuhlmiller TJ, Angus SP, Johnson GL, Nalepa G, Yates CW, Wade Clapp D, Park SJ. A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas. Hum Mol Genet 2019; 28:572-583. [PMID: 30335132 PMCID: PMC6489415 DOI: 10.1093/hmg/ddy361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/29/2018] [Accepted: 10/05/2018] [Indexed: 12/29/2022] Open
Abstract
Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.
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Affiliation(s)
- Jeffrey R Gehlhausen
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Eric Hawley
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Benjamin Mark Wahle
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yongzheng He
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Donna Edwards
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Steven D Rhodes
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jacquelyn D Lajiness
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Karl Staser
- Department of Medicine, Division of Dermatology, Washington University in Saint Louis, St. Louis, MO, USA
| | - Shi Chen
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xianlin Yang
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jin Yuan
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xiaohong Li
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Li Jiang
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Abbi Smith
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Waylan Bessler
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - George Sandusky
- Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | | | - Steven P Angus
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC
| | - Gary L Johnson
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC
| | - Grzegorz Nalepa
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Charles W Yates
- Department of Otolaryngology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - D Wade Clapp
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Su-Jung Park
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA
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39
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Marcelis L, Tousseyn T, Sagaert X. MALT Lymphoma as a Model of Chronic Inflammation-Induced Gastric Tumor Development. Curr Top Microbiol Immunol 2019; 421:77-106. [PMID: 31123886 DOI: 10.1007/978-3-030-15138-6_4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mucosa-associated lymphoid tissue (MALT) lymphoma, or extranodal marginal zone lymphoma of MALT, is an indolent B-cell non-Hodgkin lymphoma linked with preexisting chronic inflammation. The stomach is the most commonly affected organ and the MALT lymphoma pathogenesis is clearly associated with Helicobacter pylori gastroduodenitis. Inflammation induces the lymphoid infiltrates in extranodal sites, where the lymphoma then subsequently develops. Genetic aberrations arise through the release of reactive oxygen species (ROS), H. pylori-induced endonucleases, and other effects. The involvement of nuclear factor kappa B (NF-κB) pathway activation, a critical regulator of pro-inflammatory responses, further highlights the role of inflammation in gastric MALT lymphoma. The NF-κB pathway regulates key elements of normal lymphocyte function, including the transcription of proliferation-promoting and anti-apoptotic genes. Aberrant constitutive activation of NF-κB signaling can lead to autoimmunity and malignancy. NF-κB pathway activation can happen through both the canonical and non-canonical pathways and can be caused by multiple genetic aberrations such as t(11;18)(q12;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21) translocations, chronic inflammation and even directly by H. pylori-associated mechanisms. Gastric MALT lymphoma is considered one of the best models of how inflammation initiates genetic events that lead to oncogenesis, determines tumor biology, dictates clinical behavior and leads to viable therapeutic targets. The purpose of this review is to present gastric MALT lymphoma as an outstanding example of the close pathogenetic link between chronic inflammation and tumor development and to describe how this information can be integrated into daily clinical practice.
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Affiliation(s)
- Lukas Marcelis
- Translational Cell and Tissue Research Lab, Department of Imaging and Pathology, KU Leuven, Louvain, Belgium
- , O&N IV Herestraat 49 - bus 7003 24, 3000, Louvain, Belgium
| | - Thomas Tousseyn
- Translational Cell and Tissue Research Lab, Department of Imaging and Pathology, KU Leuven, Louvain, Belgium
- Department of Pathology, UZ Leuven, University Hospitals, Louvain, Belgium
- , O&N IV Herestraat 49 - bus 7003 24, 3000, Louvain, Belgium
| | - Xavier Sagaert
- Translational Cell and Tissue Research Lab, Department of Imaging and Pathology, KU Leuven, Louvain, Belgium.
- Department of Pathology, UZ Leuven, University Hospitals, Louvain, Belgium.
- , O&N IV Herestraat 49 - bus 7003 24, 3000, Louvain, Belgium.
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40
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Ruland J, Hartjes L. CARD–BCL-10–MALT1 signalling in protective and pathological immunity. Nat Rev Immunol 2018; 19:118-134. [DOI: 10.1038/s41577-018-0087-2] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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41
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Thys A, Douanne T, Bidère N. Post-translational Modifications of the CARMA1-BCL10-MALT1 Complex in Lymphocytes and Activated B-Cell Like Subtype of Diffuse Large B-Cell Lymphoma. Front Oncol 2018; 8:498. [PMID: 30474008 PMCID: PMC6237847 DOI: 10.3389/fonc.2018.00498] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 10/15/2018] [Indexed: 12/28/2022] Open
Abstract
Piracy of the NF-κB transcription factors signaling pathway, to sustain its activity, is a mechanism often deployed in B-cell lymphoma to promote unlimited growth and survival. The aggressive activated B-cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) exploits a multi-protein complex of CARMA1, BCL10, and MALT1 (CBM complex), which normally conveys NF-κB signaling upon antigen receptors engagement. Once assembled, the CBM also unleashes MALT1 protease activity to finely tune the immune response. As a result, ABC DLBCL tumors develop a profound addiction to NF-κB and to MALT1 enzyme, leaving open a breach for therapeutics. However, the pleiotropic nature of NF-κB jeopardizes the success of its targeting and urges us to develop new strategies. In this review, we discuss how post-translational modifications, such as phosphorylation and ubiquitination of the CBM components, as well as, MALT1 proteolytic activity, shape the CBM activity in lymphocytes and ABC DLBCL, and may provide new avenues to restore vulnerability in lymphoma.
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Affiliation(s)
- An Thys
- Team SOAP, CRCINA, Institut National de la Santé et de la Recherche Médicale, CNRS, Université de Nantes, Université d'Angers, Nantes, France
| | - Tiphaine Douanne
- Team SOAP, CRCINA, Institut National de la Santé et de la Recherche Médicale, CNRS, Université de Nantes, Université d'Angers, Nantes, France
| | - Nicolas Bidère
- Team SOAP, CRCINA, Institut National de la Santé et de la Recherche Médicale, CNRS, Université de Nantes, Université d'Angers, Nantes, France
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42
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Paul A, Edwards J, Pepper C, Mackay S. Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets. Cells 2018; 7:E176. [PMID: 30347849 PMCID: PMC6210445 DOI: 10.3390/cells7100176] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 10/15/2018] [Accepted: 10/17/2018] [Indexed: 12/23/2022] Open
Abstract
The cellular kinases inhibitory-κB kinase (IKK) α and Nuclear Factor-κB (NF-κB)-inducing kinase (NIK) are well recognised as key central regulators and drivers of the non-canonical NF-κB cascade and as such dictate the initiation and development of defined transcriptional responses associated with the liberation of p52-RelB and p52-p52 NF-κB dimer complexes. Whilst these kinases and downstream NF-κB complexes transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes, they also play a key role in the pathogenesis of a number of inflammatory-based conditions and diverse cancer types, which for the latter may be a result of background mutational status. IKKα and NIK, therefore, represent attractive targets for pharmacological intervention. Here, specifically in the cancer setting, we reflect on the potential pathophysiological role(s) of each of these kinases, their associated downstream signalling outcomes and the stimulatory and mutational mechanisms leading to their increased activation. We also consider the downstream coordination of transcriptional events and phenotypic outcomes illustrative of key cancer 'Hallmarks' that are now increasingly perceived to be due to the coordinated recruitment of both NF-κB-dependent as well as NF-κB⁻independent signalling. Furthermore, as these kinases regulate the transition from hormone-dependent to hormone-independent growth in defined tumour subsets, potential tumour reactivation and major cytokine and chemokine species that may have significant bearing upon tumour-stromal communication and tumour microenvironment it reiterates their potential to be drug targets. Therefore, with the emergence of small molecule kinase inhibitors targeting each of these kinases, we consider medicinal chemistry efforts to date and those evolving that may contribute to the development of viable pharmacological intervention strategies to target a variety of tumour types.
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Affiliation(s)
- Andrew Paul
- Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0NR, UK.
| | - Joanne Edwards
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.
| | - Christopher Pepper
- Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, UK.
| | - Simon Mackay
- Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0NR, UK.
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43
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Lu HY, Bauman BM, Arjunaraja S, Dorjbal B, Milner JD, Snow AL, Turvey SE. The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex. Front Immunol 2018; 9:2078. [PMID: 30283440 PMCID: PMC6156466 DOI: 10.3389/fimmu.2018.02078] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 08/22/2018] [Indexed: 01/06/2023] Open
Abstract
The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed "CBM-opathies." Clinical manifestations range from severe combined immunodeficiency to selective B cell lymphocytosis, atopic disease, and specific humoral defects. This surprisingly broad spectrum of phenotypes underscores the importance of "tuning" CBM signaling to preserve immune homeostasis. Here, we review the distinct clinical and immunological phenotypes associated with human CBM complex mutations and introduce new avenues for targeted therapeutic intervention.
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Affiliation(s)
- Henry Y Lu
- Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.,Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada
| | - Bradly M Bauman
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Swadhinya Arjunaraja
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Batsukh Dorjbal
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Joshua D Milner
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Andrew L Snow
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Stuart E Turvey
- Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.,Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada
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Juilland M, Thome M. Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling. Front Immunol 2018; 9:1927. [PMID: 30214442 PMCID: PMC6125328 DOI: 10.3389/fimmu.2018.01927] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 08/06/2018] [Indexed: 01/20/2023] Open
Abstract
The scaffold proteins CARMA1-3 (encoded by the genes CARD11, -14 and -10) and CARD9 play major roles in signaling downstream of receptors with immunoreceptor tyrosine activation motifs (ITAMs), G-protein coupled receptors (GPCR) and receptor tyrosine kinases (RTK). These receptors trigger the formation of oligomeric CARMA/CARD-BCL10-MALT1 (CBM) complexes via kinases of the PKC family. The CBM in turn regulates gene expression by the activation of NF-κB and AP-1 transcription factors and controls transcript stability. The paracaspase MALT1 is the only CBM component having an enzymatic (proteolytic) activity and has therefore recently gained attention as a potential drug target. Here we review recent advances in the understanding of the molecular function of the protease MALT1 and summarize how MALT1 scaffold and protease function contribute to the transmission of CBM signals. Finally, we will highlight how dysregulation of MALT1 function can cause pathologies such as immunodeficiency, autoimmunity, psoriasis, and cancer.
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Affiliation(s)
- Mélanie Juilland
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Margot Thome
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
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45
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Abstract
There are three different marginal zone lymphomas (MZLs): the extranodal MZL of mucosa-associated lymphoid tissue (MALT) type (MALT lymphoma), the splenic MZL, and the nodal MZL. The three MZLs share common lesions and deregulated pathways but also present specific alterations that can be used for their differential diagnosis. Although trisomies of chromosomes 3 and 18, deletions at 6q23, deregulation of nuclear factor kappa B, and chromatin remodeling genes are frequent events in all of them, the three MZLs differ in the presence of recurrent translocations, mutations affecting the NOTCH pathway, and the transcription factor Kruppel like factor 2 ( KLF2) or the receptor-type protein tyrosine phosphatase delta ( PTPRD). Since a better understanding of the molecular events underlying each subtype may have practical relevance, this review summarizes the most recent and main advances in our understanding of the genetics and biology of MZLs.
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Affiliation(s)
- Francesco Bertoni
- Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.,Oncology Institute of Southern Switzerland (IOSI), Ospedale San Giovanni, Bellinzona, Switzerland
| | - Davide Rossi
- Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.,Oncology Institute of Southern Switzerland (IOSI), Ospedale San Giovanni, Bellinzona, Switzerland
| | - Emanuele Zucca
- Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.,Oncology Institute of Southern Switzerland (IOSI), Ospedale San Giovanni, Bellinzona, Switzerland
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46
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Grondona P, Bucher P, Schulze-Osthoff K, Hailfinger S, Schmitt A. NF-κB Activation in Lymphoid Malignancies: Genetics, Signaling, and Targeted Therapy. Biomedicines 2018; 6:biomedicines6020038. [PMID: 29587428 PMCID: PMC6027339 DOI: 10.3390/biomedicines6020038] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 03/20/2018] [Accepted: 03/22/2018] [Indexed: 12/12/2022] Open
Abstract
The NF-κB transcription factor family plays a crucial role in lymphocyte proliferation and survival. Consequently, aberrant NF-κB activation has been described in a variety of lymphoid malignancies, including diffuse large B-cell lymphoma, Hodgkin lymphoma, and adult T-cell leukemia. Several factors, such as persistent infections (e.g., with Helicobacter pylori), the pro-inflammatory microenvironment of the cancer, self-reactive immune receptors as well as genetic lesions altering the function of key signaling effectors, contribute to constitutive NF-κB activity in these malignancies. In this review, we will discuss the molecular consequences of recurrent genetic lesions affecting key regulators of NF-κB signaling. We will particularly focus on the oncogenic mechanisms by which these alterations drive deregulated NF-κB activity and thus promote the growth and survival of the malignant cells. As the concept of a targeted therapy based on the mutational status of the malignancy has been supported by several recent preclinical and clinical studies, further insight in the function of NF-κB modulators and in the molecular mechanisms governing aberrant NF-κB activation observed in lymphoid malignancies might lead to the development of additional treatment strategies and thus improve lymphoma therapy.
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Affiliation(s)
- Paula Grondona
- Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Hoppe-Seyler-Str. 4, 72076 Tuebingen, Germany.
| | - Philip Bucher
- Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Hoppe-Seyler-Str. 4, 72076 Tuebingen, Germany.
| | - Klaus Schulze-Osthoff
- Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Hoppe-Seyler-Str. 4, 72076 Tuebingen, Germany.
| | - Stephan Hailfinger
- Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Hoppe-Seyler-Str. 4, 72076 Tuebingen, Germany.
| | - Anja Schmitt
- Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Hoppe-Seyler-Str. 4, 72076 Tuebingen, Germany.
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47
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Abstract
PURPOSE OF REVIEW The purpose of the study is to summarize the current conundrums in the management of marginal zone lymphomas (MZL). RECENT FINDINGS In 2017, the US Food and Drug Administration (FDA) approved ibrutinib, a first in class Bruton Tyrosine Kinase inhibitor, for the treatment of relapsed/refractory MZL based on pivotal open-label phase II trial demonstrating an overall response rates of 48%. Clinical trials design utilizing chemotherapy-free regimens for relapsed/refractory disease are gaining popularity. Recent studies have identified multiple genetic biomarkers that helped characterize and prognosticate different subtypes of MZL. MZLs are heterogeneous, mostly indolent, malignancies derived from B lymphocytes. Three disease subtypes are recognized, extranodal, nodal, and splenic. The disease characteristics, clinical picture, and treatment algorithms vary considerably based on subtype and site of involvement. Recent discoveries have enhanced our knowledge of the pathogenesis of MZLs leading to development of more accurate prognostic models as well as novel targeted systemic therapies.
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48
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Rentien AL, Lévy M, Copie-Bergman C, Gagniere C, Dupuis J, Le Baleur Y, Belhadj K, Sobhani I, Haioun C, Delchier JC, Amiot A. Long-term course of precancerous lesions arising in patients with gastric MALT lymphoma. Dig Liver Dis 2018; 50:181-188. [PMID: 29102522 DOI: 10.1016/j.dld.2017.10.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/11/2017] [Accepted: 10/13/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS To evaluate the prevalence and the long-term course of gastric precancerous lesions in patients with GML. PATIENTS AND METHODS In this retrospective single-centre study, we included 179 patients with GML, 70 with gastric diffuse large B-cell lymphoma (GDLBCL) and 152 with Helicobacter pylori-associated gastritis (HpG), from January 1995 to January 2014. The presence of atrophic gastritis, intestinal metaplasia and neoplastic lesion has been assessed at baseline and during follow-up. RESULTS Atrophic gastritis was more frequent in the GML group whereas there was also a trend for intestinal metaplasia and gastric dysplasia. In patients with GML, atrophic gastritis, intestinal metaplasia and gastric dysplasia were more frequent in the GML area than in other part of the stomach. During follow-up, the prevalence of atrophic gastritis remained stable overtime whereas intestinal metaplasia and dysplasia tend to increase overtime. In multivariate analysis, the occurrence of dysplasia or carcinoma was associated with the presence of intestinal metaplasia at baseline and male gender. CONCLUSION GML is associated with gastric precancerous lesion to a higher extent than GDLBCL and HpG. Those precancerous lesions do not regress despite achievement of complete remission of GML and tend to increase overtime.
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Affiliation(s)
- Anne-Laure Rentien
- Department of Gastroenterology, Henri Mondor University Hospital, APHP, Creteil F-94010, France; Paris Est-Creteil University (UPEC), Creteil F-94010, France; EC2M3-EA7375 Unit, Creteil, France
| | - Michaël Lévy
- Department of Gastroenterology, Henri Mondor University Hospital, APHP, Creteil F-94010, France
| | - Christiane Copie-Bergman
- Paris Est-Creteil University (UPEC), Creteil F-94010, France; Department of Pathology, Henri Mondor University Hospital, APHP, Creteil F-94010, France; Unit UMR-S 955, INSERM, Creteil F-94010, France
| | - Charlotte Gagniere
- Department of Gastroenterology, Henri Mondor University Hospital, APHP, Creteil F-94010, France; Paris Est-Creteil University (UPEC), Creteil F-94010, France; EC2M3-EA7375 Unit, Creteil, France
| | - Jehan Dupuis
- Lymphoid Malignancies Unit, Henri Mondor University Hospital, APHP, Creteil F-94010, France
| | - Yann Le Baleur
- Department of Gastroenterology, Henri Mondor University Hospital, APHP, Creteil F-94010, France
| | - Karim Belhadj
- Lymphoid Malignancies Unit, Henri Mondor University Hospital, APHP, Creteil F-94010, France
| | - Iradj Sobhani
- Department of Gastroenterology, Henri Mondor University Hospital, APHP, Creteil F-94010, France
| | - Corinne Haioun
- Paris Est-Creteil University (UPEC), Creteil F-94010, France; Unit UMR-S 955, INSERM, Creteil F-94010, France; Lymphoid Malignancies Unit, Henri Mondor University Hospital, APHP, Creteil F-94010, France
| | - Jean-Charles Delchier
- Department of Gastroenterology, Henri Mondor University Hospital, APHP, Creteil F-94010, France; Paris Est-Creteil University (UPEC), Creteil F-94010, France
| | - Aurelien Amiot
- Department of Gastroenterology, Henri Mondor University Hospital, APHP, Creteil F-94010, France; Paris Est-Creteil University (UPEC), Creteil F-94010, France; EC2M3-EA7375 Unit, Creteil, France.
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49
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Ramos CA. Marginal Zone Lymphomas (Extranodal/Malt, Splenic, and Nodal). Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00079-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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50
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Burkitt MD, Duckworth CA, Williams JM, Pritchard DM. Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models. Dis Model Mech 2017; 10:89-104. [PMID: 28151409 PMCID: PMC5312008 DOI: 10.1242/dmm.027649] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastric colonization with Helicobacter pylori induces diverse human pathological conditions, including superficial gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma and its precursors. The treatment of these conditions often relies on the eradication of H. pylori, an intervention that is increasingly difficult to achieve and that does not prevent disease progression in some contexts. There is, therefore, a pressing need to develop new experimental models of H. pylori-associated gastric pathology to support novel drug development in this field. Here, we review the current status of in vivo and ex vivo models of gastric H. pylori colonization, and of Helicobacter-induced gastric pathology, focusing on models of gastric pathology induced by H. pylori, Helicobacter felis and Helicobacter suis in rodents and large animals. We also discuss the more recent development of gastric organoid cultures from murine and human gastric tissue, as well as from human pluripotent stem cells, and the outcomes of H. pylori infection in these systems.
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Affiliation(s)
- Michael D Burkitt
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK
| | - Carrie A Duckworth
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK
| | - Jonathan M Williams
- Pathology and Pathogen Biology, Royal Veterinary College, North Mymms AL9 7TA, UK
| | - D Mark Pritchard
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK
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