Knittel, Gero, Liedgens, Paul, Korovkina, Darya, Seeger, Jens M., Al-Baldawi, Yussor, Al-Maarri, Mona, Fritz, Christian, Vlantis, Katerina, Bezhanova, Svetlana ORCID: 0000-0001-7336-9210, Scheel, Andreas H., Wolz, Olaf-Oliver, Reimann, Maurice, Moeller, Peter, Lopez, Cristina ORCID: 0000-0001-6644-1659, Schlesner, Matthias ORCID: 0000-0002-5896-4086, Lohneis, Philipp, Weber, Alexander N. R., Truemper, Lorenz, Staudt, Louis M., Ortmann, Monika, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Siebert, Reiner, Schmitt, Clemens A., Klatt, Andreas R., Wunderlich, F. Thomas, Schaefer, Stephan C., Persigehl, Thorsten, Montesinos-Rongen, Manuel, Odenthal, Margarete, Buettner, Reinhard, Frenzel, Lukas P., Kashkar, Hamid and Reinhardt, H. Christian (2016). B-cell-specific conditional expression of Myd88(p.L252P) leads to the development of diffuse large B-cell lymphoma in mice. Blood, 127 (22). S. 2732 - 2742. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-kappa B activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-kappa B pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2. Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Knittel, GeroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liedgens, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korovkina, DaryaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger, Jens M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Baldawi, YussorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Maarri, MonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritz, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vlantis, KaterinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bezhanova, SvetlanaUNSPECIFIEDorcid.org/0000-0001-7336-9210UNSPECIFIED
Scheel, Andreas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolz, Olaf-OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reimann, MauriceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moeller, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez, CristinaUNSPECIFIEDorcid.org/0000-0001-6644-1659UNSPECIFIED
Schlesner, MatthiasUNSPECIFIEDorcid.org/0000-0002-5896-4086UNSPECIFIED
Lohneis, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Alexander N. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Truemper, LorenzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Staudt, Louis M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortmann, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Siebert, ReinerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, Clemens A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klatt, Andreas R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, F. ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, Stephan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montesinos-Rongen, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, Lukas P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-272547
DOI: 10.1182/blood-2015-11684183
Journal or Publication Title: Blood
Volume: 127
Number: 22
Page Range: S. 2732 - 2742
Date: 2016
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
IDENTIFIES RECURRENT MUTATIONS; WALDENSTROM MACROGLOBULINEMIA; SOMATIC MUTATION; GERMINAL CENTER; MYD88 L265P; GENE; DIFFERENTIATION; CLASSIFICATION; ACTIVATION; DISORDERSMultiple languages
HematologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27254

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