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Ferrata Storti Foundation
Non-Hodgkin Lymphoma
Identification of the atypically modified autoantigen Ars2 as the target of B-cell receptors from activated B-cell-type diffuse large B-cell lymphoma
Lorenz Thurner,1 Sylvia Hartmann,2 Moritz Bewarder,1 Natalie Fadle,1 Evi Regitz,1 Claudia Schormann,1 Natalia Quiroga,1 Maria Kemele,1 Wolfram Klapper,3 Andreas Rosenwald,4 Lorenz Trümper,5 Rainer Maria Bohle,6 Anna Nimmesgern,7 Christina Körbel,8 Matthias W. Laschke,8 Michael D. Menger,8 Stefan Barth,9 Boris Kubuschok,10 Anja Mottok,11 Dominic Kaddu-Mulindwa,1 Martin-Leo Hansmann,2 Viola Pöschel,1 Gerhard Held,12 Niels Murawski,1 Stephan Stilgenbauer,1 Frank Neumann,1 Klaus-Dieter Preuss1 and Michael Pfreundschuh1
Haematologica 2021 Volume 106(8):2224-2232
1Saarland University Medical School, José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Homburg/Saar, Germany; 2Dr. Senckenberg Institute of Pathology, Goethe University Hospital of Frankfurt am Main, Frankfurt am Main, Germany; 3Institute of Pathology, University of Kiel, Kiel, Germany; 4Institute of Pathology, University of Würzburg and CCC Mainfranken, Würzburg, Germany; 5Department of Hematology and Medical Oncology, University Hospital Göttingen, Göttingen, Germany; 6Saarland University Medical School, Institute of Pathology, Homburg/Saar, Germany; 7Institute of Medical Microbiology and Hygiene, University of Saarland, Homburg, Germany; 8Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany; 9Institute for Infectious disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa; 10Department of Internal Medicine II, Augsburg University Medical Center, Augsburg, Germany; 11Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany and 12Department of Hematology/Oncology, Westpfalzklinikum, Kaiserslautern, Germany
Deceased.
ABSTRACT
It has been suggested that stimulation of B-cell receptors (BCR) by specific antigens plays a pathogenic role in diffuse large B-cell lym- phoma (DLBCL). Here, it was the aim to screen for specific reactivi- ties of DLBCL-BCR in the spectrum of autoantigens and antigens of infectious origin. Arsenite resistance protein 2 (Ars2) was identified as the BCR target of three of five activated B-cell type DLBCL cell lines and two of 11 primary DLBCL cases. Compared to controls, Ars2 was hypophosphorylated exclusively in cases and cell lines with Ars2-specif- ic BCR. In a validation cohort, hypophosphorylated Ars2 was found in eight of 31 activated B-cell type DLBCL, but in only one of 20 germinal center B-cell like type DLBCL. Incubation with Ars2 induced BCR-path- way activation and increased proliferation, while an Ars2/ETA’ toxin conjugate induced killing of cell lines with Ars2-reactive BCR. Ars2 appears to play a role in a subgroup of activated B-cell-type DLBCL. Moreover, transformed DLBCL lines with Ars2-reactive BCR still showed growth advantage after incubation with Ars2. These results provide knowledge about the pathogenic role of a specific antigen stim- ulating the BCR pathway in DLCBL.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell non- Hodgkin lymphoma. According to the World Health Organization (WHO) classifica- tion, DLBCL can be classified based on gene expression profiling (GEP) into an acti- vated B-cell (ABC)-like type, a germinal center B-cell (GCB)-like type and primary mediastinal B-cell lymphoma.1,2 In contrast to relatively well-studied genetic or epige- netic pathway alterations, little is known about specific and complementary external
Correspondence:
LORENZ THURNER
lorenz.thurner@uks.eu
Received: October 28, 2019. Accepted: July 9, 2020. Pre-published: July 16, 2020.
https://doi.org/10.3324/haematol.2019.241653
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