Review
Biochemistry & Molecular Biology
Marco Cippitelli, Helena Stabile, Andrea Kosta, Sara Petillo, Lorenzo Lucantonio, Angela Gismondi, Angela Santoni, Cinzia Fionda
Summary: Nuclear factor-kappa B (NF-kappa B) transcription factors are crucial in the pathogenesis of multiple myeloma (MM). The activation of canonical and noncanonical NF-kappa B pathways, triggered by mutations or the production of cytokines and growth factors, supports the survival, proliferation, and chemoresistance of malignant plasma cells. NF-kappa B also affects the activity of noncancerous cells, including mesenchymal stromal cells (MSCs), which play a critical role in disease progression and the interplay between MSCs and MM cells. This review aims to analyze the role of NF-kappa B in MM, focusing on NF-kappa B-dependent mechanisms in tumor cells, MSCs, and their crosstalk.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Chunmin Ma, Meng Liu, Jiong Zhang, Haiyan Cai, Yunzhao Wu, Ying Zhang, Yanjie Ji, Huizhuang Shan, Zhihui Zou, Li Yang, Ligen Liu, Hanzhang Xu, Hu Lei, Chuanxu Liu, Li Zhou, Yang Cao, Huchen Zhou, Yingli Wu
Summary: The study found that ZCL-082 is a highly promising anti-lymphoma compound that targets RSK1 and interferes with the RSK1/NF-kappa B signaling pathway. The combination of ZCL-082 with BCL-2 inhibitor may represent a novel strategy to improve the outcome of double-hit or double-expressor lymphoma.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Article
Immunology
Yu Rebecca Miao, Kaushik Thakkar, Can Cenik, Dadi Jiang, Kazue Mizuno, Chenjun Jia, Caiyun Grace Li, Hongjuan Zhao, Anh Diep, Yu Xu, Xin Eric Zhang, Teddy Tat Chi Yang, Michaela Liedtke, Parveen Abidi, Wing-Sze Leung, Albert C. Koong, Amato J. Giaccia
Summary: This study reveals the distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF in hematological cancers, and demonstrates that an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) significantly enhances antitumor activity against both MM and DLBCL. The study also shows an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Genetics & Heredity
Min-Yue Zhang, George Calin, Ming-Dan Deng, Rex K. H. Au-Yeung, Lu-Qian Wang, Chor-Sang Chim
Summary: This study investigated the function and mechanism of long non-coding RNA NKILA in non-Hodgkin's lymphoma. They found that NKILA was methylated in tumor cell lines, leading to the loss of its tumor suppressor effect and sustained activation of NF-kappa B signaling. The results suggest that NKILA is an important tumor suppressor in DLBCL.
Article
Oncology
Thomas A. Burley, Emma Kennedy, Georgia Broad, Melanie Boyd, David Li, Timothy Woo, Christopher West, Eleni E. Ladikou, Iona Ashworth, Christopher Fegan, Rosalynd Johnston, Simon Mitchell, Simon P. Mackay, Andrea G. S. Pepper, Chris Pepper
Summary: In this study, the researchers evaluated the effects of an NF-kappa B inducing kinase (NIK) inhibitor, CW15337, on primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines, and normal B- and T-lymphocytes. They found that CW15337 induced apoptosis and inhibited the non-canonical NF-kappa B signaling pathway, reversing BCL2 family-mediated resistance. The combination of CW15337 with fludarabine or ABT-199 showed synergistic cytotoxic effects.
Article
Oncology
Melody Caillot, Hadjer Miloudi, Antoine Taly, Nuria Profitos-Peleja, Juliana C. Santos, Marcelo L. Ribeiro, Elsa Maitre, Simon Saule, Gael Roue, Fabrice Jardin, Brigitte Sola
Summary: By studying the impact of XPO1 gene mutation on protein function, it was found that the mutation renders lymphoma cells more sensitive to SINEs drugs. Additionally, the mutation also leads to mistrafficking of transcription factors between the nucleus and cytoplasm, affecting the response to ibrutinib.
MOLECULAR ONCOLOGY
(2023)
Article
Hematology
Anja Schmitt, Wendan Xu, Philip Bucher, Melanie Grimm, Martina Konantz, Heike Horn, Myroslav Zapukhlyak, Philipp Berning, Marc Braendle, Mohamed-Ali Jarboui, Caroline Sch Onfeld, Karsten Boldt, Andreas Rosenwald, German Ott, Michael Grau, Pavel Klener, Petra Vockova, Claudia Lengerke, Georg Lenz, Klaus Schulze-Osthoff, Stephan Hailfinger
Summary: The study demonstrates the broad antitumor effect of dimethyl fumarate (DMF) on both subtypes of DLBCL by inducing ferroptosis, especially in GCB DLBCL. In ABC DLBCL cells, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Additionally, the combination of BCL-2-specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL.
Article
Immunology
Kristin Roseth Aass, Synne Stokke Tryggestad, Robin Mjelle, Martin H. H. Kastnes, Tonje Marie Vikene Nedal, Kristine Misund, Therese Standal
Summary: Multiple myeloma is a type of cancer characterized by the accumulation of malignant plasma cells in the bone marrow. Interleukin-32 (IL-32), a pro-inflammatory cytokine, is expressed in a subgroup of multiple myeloma patients and has been shown to promote the proliferation and survival of cancer cells. This study demonstrates that activation of Toll-like receptors (TLRs) can induce the expression of IL-32 in multiple myeloma cells through NF kappa B activation. The upregulation of TLR genes in individual patients, particularly those sensing bacterial components, coincides with an increase in IL-32 expression, suggesting that infections can induce the expression of this pro-tumorigenic cytokine in multiple myeloma patients.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Arshiya Parveen, Kyle R. Bohnert, Meiricris Tomaz da Silva, Yefei Wen, Raksha Bhat, Anirban Roy, Ashok Kumar
Summary: The study demonstrates the important role of the MyD88 signaling pathway in denervation-induced muscle wasting, potentially through influencing NF-kappa B, AMPK, and UPR pathways.
Article
Oncology
Ruosi Yao, Yan Zhang, Yindi Zeng, Yaxin Zhang, Linlin Liu, Jian Gao
Summary: Multiple myeloma (MM) is an incurable disease characterized by excessive proliferation of bone marrow plasma cells and production of abnormal immunoglobulins. Drug resistance remains a major obstacle in MM therapy, calling for the development of novel agents. A study has demonstrated that the compound EP12 effectively inhibits primary myeloma growth in vivo by destabilizing c-Myc and disrupting the NF-κB signaling pathway. These findings suggest that EP12 holds promise as a therapeutic agent for MM as a potent c-Myc inhibitor.
EXPERIMENTAL CELL RESEARCH
(2023)
Article
Oncology
Barbara Kiesewetter, Christiane Copie-Bergman, Michael Levy, Fangtian Wu, Jehan Dupuis, Caroline Barau, Luca Arcaini, Marco Paulli, Marco Lucioni, Arturo Bonometti, Antonio Salar, Concepcion Fernandez-Rodriguez, Miguel A. Piris, Francesco Cucco, Rachel Dobson, Yan Li, Zi Chen, Cyrielle Robe, Ingrid Simonitsch-Klupp, Andrew Wotherspoon, Markus Raderer, Ming Qing Du
Summary: The study reveals that H. pylori negative gastric MALT lymphoma is characterized by frequent genetic changes in the NF-kappa B signaling pathways. However, these genetic changes do not show significant correlation with clinicopathological parameters, and patients treated with systemic therapy have significantly better progression-free survival compared to those treated with antibiotics.
Article
Oncology
Yuan Chen, Xianglei Chen, Lili Pan, Yuanmao Huang, Yuanhua Cai, Jinggang Li, Yang Li, Shaoyuan Wang
Summary: DHX15 is overexpressed in Burkitt lymphoma and is associated with poor prognosis. Knockdown of DHX15 inhibits tumor growth and increases cell apoptosis. In addition, DHX15 knockdown reduces EBV latent infection products expression and inhibits RNA polymerase III activity.
CANCER CELL INTERNATIONAL
(2022)
Article
Oncology
Hua Zhang, Jintong Chen, Mingyue Zhang, Munan Zhao, Luyao Zhang, Bin Liu, Siqing Wang
Summary: This study found that tetrahydrobiopterin (BH4) promotes tumor growth and drug resistance in multiple myeloma (MM). BH4 increases the expression of USP7 and USP46, leading to the degradation of P53 and the activation of NF-kappa B signaling. Inhibition of USPs enhances the therapeutic effects of bortezomib in MM. These findings highlight the important role of BH4 in MM drug resistance and tumor progression.
Editorial Material
Biochemistry & Molecular Biology
Elizabeth M. Black, Yoon Ki Joo, Lilia Kabeche
Summary: Chk1 is a crucial player in the DNA damage response pathway and its loss can lead to replication stress and genome instability. However, the development of resistance to Chk1 inhibitors remains a major challenge in cancer therapy. Recent studies have shed light on multiple mechanisms underlying the emergence of Chk1 inhibitor resistance in lymphomas, involving dysfunction in NF-kappa B and up-regulation of alternative pathways. Additionally, these studies have discovered a novel role for Claspin in female fertility and cancer development, further deepening our understanding of the impact of dysfunction in the Claspin/Chk1 signaling pathway on disease states.
BIOCHEMICAL JOURNAL
(2022)
Article
Multidisciplinary Sciences
Koen Debackere, Lukas Marcelis, Sofie Demeyer, Marlies Vanden Bempt, Nicole Mentens, Olga Gielen, Kris Jacobs, Michael Broux, Gregor Verhoef, Lucienne Michaux, Carlos Graux, Iwona Wlodarska, Philippe Gaulard, Laurence de Leval, Thomas Tousseyn, Jan Cools, Daan Dierickx
Summary: This study identifies two fusion transcripts that activate T cell receptor complex signaling and confer therapeutic vulnerability in PTCL-NOS, contributing to the understanding of this poorly characterized subgroup of PTCL at the genetic level.
NATURE COMMUNICATIONS
(2021)
Article
Allergy
Necil Kutukculer, Thomas Seeholzer, Thomas J. O'Neill, Carina Grass, Ayca Aykut, Neslihan Edeer Karaca, Asude Durmaz, Ozgur Cogulu, Guzide Aksu, Torben Gehring, Andreas Gewies, Daniel Krappmann
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Hongli Yin, Ozge Karayel, Ying-Yin Chao, Thomas Seeholzer, Isabel Hamp, Oliver Plettenburg, Torben Gehring, Christina Zielinski, Matthias Mann, Daniel Krappmann
Summary: This study found that ABIN-1 modulates the suppressive function of A20 in T cells, and revealed that the A20/ABIN-1 module regulates CBM complex signaling and T cell activation through the interaction between A20 ZnF4/7 and the CBM complex.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Immunology
Asena Pinar Sefer, Hassan Abolhassani, Franziska Ober, Basak Kayaoglu, Sevgi Bilgic Eltan, Altan Kara, Baran Erman, Naz Surucu Yilmaz, Cigdem Aydogmus, Sezin Aydemir, Louis-Marie Charbonnier, Burcu Kolukisa, Gholamreza Azizi, Samaneh Delavari, Tooba Momen, Simuzar Aliyeva, Yasemin Kendir Demirkol, Saban Tekin, Ayca Kiykim, Omer Faruk Baser, Haluk Cokugras, Mayda Gursel, Elif Karakoc-Aydiner, Ahmet Ozen, Daniel Krappmann, Talal A. Chatila, Nima Rezaei, Safa Baris
Summary: This study analyzed the clinical and immunological features of MALT1 deficiency and found that the main characteristics of the disease are recurrent infections, eczema, chronic diarrhea, and failure to thrive. Most patients had normal T and NK cells, while B cells were reduced. Immunoglobulin replacement therapy and antibiotic prophylaxis were ineffective. HSCT may be a curative therapeutic option for all patients at the early stage of life.
JOURNAL OF CLINICAL IMMUNOLOGY
(2022)
Article
Dermatology
Y. Amar, E. Schneider, M. Koberle, T. Seeholzer, S. Musiol, I. M. Hoelge, S. Gschwendtner, D. Krappmann, K. Steiger, T. Biedermann, C. B. Schmidt-Weber, F. Alessandrini
Summary: This study analyzed the skin microbiome of two commonly used murine models for atopic dermatitis (AD) and found similarities in dysbiosis with human AD. These findings are important for translational research on AD with a focus on the microbiome.
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
(2022)
Article
Oncology
Jia-Ying Lloyd Lee, Prasanna Ekambaram, Neil M. Carleton, Dong Hu, Linda R. Klei, Zongyou Cai, Max Myers, Nathaniel E. Hubel, Lidija Covic, Sameer Agnihotri, Daniel Krappmann, Frederic Bornancin, Adrian Lee, Steffi Oesterreich, Linda M. McAllister-Lucas, Peter C. Lucas
Summary: MALT1 is the effector protein in the CARMA/Bcl10/MALT1 inflammatory signaling pathways, playing a key role in EMT in immune cells and solid tumors, particularly in TNBC, where its signaling blockade can partially reverse EMT.
MOLECULAR CANCER RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Kerstin Kutzner, Simone Woods, Ozge Karayel, Torben Gehring, Hongli Yin, Andrew Flatley, Carina Grass, Nicole Wimberger, Marie J. Tofaute, Thomas Seeholzer, Regina Feederle, Matthias Mann, Daniel Krappmann
Summary: This study demonstrates that PKC theta/beta phosphorylation plays a dual role in regulating CARD11 signaling in lymphocytes: promoting the assembly of the CARD11-BCL10-MALT1 complex and lymphocyte activation, while also suppressing CARD11 function. Phosphorylation of Ser 893 in CARD11 prevents the activation of NF-kappa B, JNK, and MALT1, and sensitizes BCR-addicted lymphoma cells to BTK inhibitors by impairing the formation of the CBM complex.
Article
Multidisciplinary Sciences
Alisha N. Jones, Carina Grass, Isabel Meininger, Arie Geerlof, Melina Klostermann, Kathi Zarnack, Daniel Krappmann, Michael Sattler
Summary: This study shows that alternative splicing of MALT1 depends on RNA structural elements that sequester the splice sites of the alternatively spliced exon7, and is regulated by competitive binding of RBPs hnRNP U and hnRNP L.
Article
Biotechnology & Applied Microbiology
Dae-Kyum Kim, Benjamin Weller, Chung-Wen Lin, Dayag Sheykhkarimli, Jennifer J. Knapp, Guillaume Dugied, Andreas Zanzoni, Carles Pons, Marie J. Tofaute, Sibusiso B. Maseko, Kerstin Spirohn, Florent Laval, Luke Lambourne, Nishka Kishore, Ashyad Rayhan, Mayra Sauer, Veronika Young, Hridi Halder, Nora Marin-de la Rosa, Oxana Pogoutse, Alexandra Strobel, Patrick Schwehn, Roujia Li, Simin T. Rothballer, Melina Altmann, Patricia Cassonnet, Atina G. Cote, Lena Elorduy Vergara, Isaiah Hazelwood, Betty B. Liu, Maria Nguyen, Ramakrishnan Pandiarajan, Bushra Dohai, Patricia A. Rodriguez Coloma, Juline Poirson, Paolo Giuliana, Luc Willems, Mikko Taipale, Yves Jacob, Tong Hao, David E. Hill, Christine Brun, Jean-Claude Twizere, Daniel Krappmann, Matthias Heinig, Claudia Falter, Patrick Aloy, Caroline Demeret, Marc Vidal, Michael A. Calderwood, Frederick P. Roth, Pascal Falter-Braun
Summary: A study mapping the contactome between SARS-CoV-2 and human host proteins uncovers an inhibitor of viral replication and connects it to COVID-19 severity and human genetic architecture, providing important insights for therapy design and drug development.
NATURE BIOTECHNOLOGY
(2022)
Review
Oncology
Thorsten R. Mempel, Daniel Krappmann
Summary: MALT1 protease has dual effects in the tumor microenvironment, inhibiting cancer cell growth and neutralizing immunosuppression. Targeting MALT1 can enhance the efficacy of cancer immunotherapy.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2022)
Article
Immunology
Ying-Yin Chao, Alisa Puhach, David Frieser, Mahima Arunkumar, Laurens Lehner, Thomas Seeholzer, Albert Garcia-Lopez, Marlot van der Wal, Silvia Fibi-Smetana, Axel Dietschmann, Thomas Sommermann, Tamara Cikovic, Leila Taher, Mark S. Gresnigt, Sebastiaan J. Vastert, Femke van Wijk, Gianni Panagiotou, Daniel Krappmann, Olaf Gross, Christina E. Zielinski
Summary: In this study, it was discovered that human T cells express GSDME, which is associated with durable viability and the release of IL-1 alpha. This property is only present in a subset of human helper type 17 T cells with specificity for Candida albicans, regulated by the T cell-intrinsic NLRP3 inflammasome. The release of IL-1 alpha is mediated by a proteolytic cascade involving caspase-8, caspase-3, and GSDME cleavage, as well as T cell receptor stimulation and calcium-licensed calpain maturation of pro-IL-1 alpha form. This finding expands our understanding of the functional diversity and mechanism of T cells and has implications for antifungal immunity.
Article
Immunology
Thomas J. O'Neill, Andreas Gewies, Thomas Seeholzer, Daniel Krappmann
Summary: MALT1 is a core component of the CBM signalosome, acting as a scaffold and protease. It connects TCR ligation to immune activation and controls the development of Treg cells. TRAF6 ablation leads to activation of Tconv cells, while MALT1 protease inactivation prevents autoinflammation.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Oncology
Thomas J. O'Neill, Marie J. Tofaute, Daniel Krappmann
Summary: MALT1 is a key regulator of immune signaling and promotes tumor development through intrinsic and extrinsic mechanisms. It acts as a scaffolding protein and protease in lymphocytes, driving NF-kappa B activation and modulating signaling. Aberrant MALT1 activity is critical for the survival and proliferation of cancer cells, and inhibiting MALT1 offers unique therapeutic opportunities.
CANCER TREATMENT REVIEWS
(2023)
Meeting Abstract
Immunology
Asena Pinar Sefer, Hassan Abolhassani, Basak Kayaoglu, Franziska Ober, Sevgi Bilgic-Eltan, Altan Kara, Baran Erman, Naz Surucu-Yilmaz, Cigdem Aydogmus, Sezin Aydemir, Louis-Marie Charbonnier, Burcu Kolukisa, Gholamreza Azizi, Samaneh Delavari, Tooba Momen, Simuzar Aliyeva, Yasemin Kendir-Demirkol, Saban Tekin, Ayca Kiykim, Omer Faruk Beser, Haluk Cokugras, Mayda Gursel, Elif Karakoc Aydiner, Ahmet Ozen, Daniel Krappmann, Talal A. Chatila, Nima Rezaei, Safa Baris
JOURNAL OF CLINICAL IMMUNOLOGY
(2022)
Article
Biology
Thomas J. O'Neill, Daniel Krappmann, Andreas Gewies
Summary: CRISPR-Cas9 genome editing in single-cell mouse zygotes has low efficiency for complex modifications, so targeting and validation in murine embryonic stem cells (ESCs) with subsequent injection into early-stage mouse embryos is preferred. This reduces animal numbers and complies with animal welfare regulations.
Meeting Abstract
Dermatology
Y. Amar, E. Schneider, M. Koeberle, T. Seeholzer, S. Musiol, I. M. Hoelge, S. Gschwendtner, D. Krappmann, T. Biedermann, C. Schmidt-Weber, F. Alessandrini
EXPERIMENTAL DERMATOLOGY
(2022)