LRPAP1 autoantibodies in mantle cell lymphoma are associated with superior outcome

Thurner, Lorenz; Fadle, Natalie; Bittenbring, Jörg; Regitz, Evi; Schück, R; Cetin, Onur; Stuhr, Ariane; Rixecker, Torben; Murawski, Niels; Poeschel, Viola; Kaddu‐Mulindwa, Dominic; Preuss, Klaus‐Dieter; Stilgenbauer, Stephan; Hermine, Olivier; Kluin‐Nelemans, Hanneke C.; Hartmann, Sylvia; Dreyling, Martin; Pott, Christiane; Bewarder, Moritz; Hoster, Eva

doi:10.1182/blood.2020008835

Cited by 10 publications

(13 citation statements)

References 30 publications

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“…Chronic active BCR signal in MCL is generally considered active. IGH-V restriction in MCL suggests self-antigen-driven BCR signal activation and a part of patients with MCL harbors LRPAP1 self-antibody [35]. SOX11 overexpression and CXCR4-dependent microenvironment interaction are considered important for BCR signal activation [36].…”

Section: Discussionmentioning

confidence: 99%

miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma

Kawaji-Kanayama

Tsukamoto

Nakano

et al. 2023

Preprint

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B-cell receptor (BCR) signaling is critically activated and targetable for mantle cell lymphoma (MCL); however, the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. This study revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. Pulldown-seq, where mRNA was captured using biotinylated miRNA transfection, was performed and analyzed with next-generation sequencing. Additionally, novel miRNA targets, including tumor suppressors such as BTG2, were identified to comprehensively define miR-17-92 cluster targets. Notably, gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with those of BCR signature genes. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL.

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Section: Discussionmentioning

confidence: 99%

miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma

Kawaji-Kanayama

Tsukamoto

Nakano

et al. 2023

Preprint

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show abstract

“…The chronic active BCR signal in MCL is generally considered active. IGH‐V restriction in MCL suggests self‐antigen‐driven BCR signal activation and some patients with MCL harbor LRPAP1 self‐antibody 38 . SOX11 overexpression and CXCR4‐dependent microenvironment interaction are considered important for BCR signal activation 39 .…”

Section: Discussionmentioning

confidence: 99%

miR‐17‐92 cluster‐BTG2 axis regulates B‐cell receptor signaling in mantle cell lymphoma

Kawaji‐Kanayama,

Tsukamoto,

Nakano

et al. 2023

Cancer Science

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B‐cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR‐17‐92 cluster remains unclear although the oncogenic microRNA (miRNA) miR‐17‐92 cluster is highly expressed in patients with MCL. We revealed that miR‐17‐92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR‐17‐92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR‐17‐92 cluster target genes, we performed pulldown‐seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead‐coated streptavidin, and quantified using next‐generation sequencing. The pulldown‐seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR‐19b), CDKN2A (miR‐17), SYNE1 (miR‐20a), TET2 (miR‐18, miR‐19b, and miR‐92a), TNFRSF10A (miR‐92a), and TRAF3 (miR‐17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR‐17‐92 cluster‐activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.

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“…Regarding more aggressive lymphomas, LRPAP1 was found to be a frequent antigen of the BCRs on mantle cell lymphoma (MCL) including the cell lines MAVER1 and Z138. In a retrospective analysis of the younger and elderly European MCL‐trials, the presence of LRPAP1‐autoantibodies was a surrogate marker for superior outcome under immunochemotherapy [ 24 , 25 ]. For primary central nervous system lymphoma (PCNSL), which is a specific extra‐nodal subtype of DLBCL with molecular similarities to MCD type or C5 with frequent mutations in MYD88 and CD79B [ 26 , 27 ], SAMD14/neurabin‐I were recently identified by us as an antigen of the BCRs.…”

Section: Introductionmentioning

confidence: 99%

B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens

Bock

Bewarder

Cetin

et al. 2022

eJHaem

Self Cite

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Burkitt lymphoma (BL) represents the most aggressive B-cell-lymphoma. Beside the hallmark of IG-MYC-translocation, surface B-cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra-nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum, a custom-made virome array and against self-antigens, including post-translationally modified antigens.An atypically modified, SUMOylated isoform of Bystin, that is, SUMO1-BYSL was identified as the antigen of the BCR of cell line CA46. SUMO1-BYSL was exclusively expressed in CA46 cells with K139 as site of the SUMOylation. Secondly, an

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LRPAP1 autoantibodies in mantle cell lymphoma are associated with superior outcome

Cited by 10 publications

References 30 publications

miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma

miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma

miR‐17‐92 cluster‐BTG2 axis regulates B‐cell receptor signaling in mantle cell lymphoma

B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens

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