An inducible <i>Cd79b</i> mutation confers ibrutinib sensitivity in mouse models of <i>Myd88</i>-driven diffuse large B-cell lymphoma
Ruth Flümann, Julia Hansen, Jörn Meinel, Pauline Pfeiffer, Hannah Goldfarb Wittkopf, Anna Lutz, Julius M Wirtz, Michael Möllmann, Tanja Zhou, Areya Tabatabai, Tim Lohmann, Maximilian Jauch, Filippo Beleggia, Benedikt W. Pelzer, Fabian Ullrich, Svenja Höfmann, Aastha Arora, Thorsten Persigehl, Reinhard Büttner, Bastian von Tresckow, Sebastian Klein, Ron D. Jachimowicz, Hans Christian Reinhardt, Gero Knittel
Abstract
ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and constitutes a highly heterogenous disease. Recent comprehensive genomic profiling revealed the identity of numerous molecularly defined DLBCL subtypes, including a cluster which is characterized by recurrent aberrations in MYD88, CD79B, and BCL2, as well as various lesions promoting a block in plasma cell differentiation, including PRDM1, TBL1XR1, and SPIB. Here, we generated a series of autochthonous mouse models to mimic this DLBCL cluster and specifically focused on the impact of Cd79b mutations in this setting. We show that canonical Cd79b immunoreceptor tyrosine-based activation motif (ITAM) mutations do not accelerate Myd88- and BCL2-driven lymphomagenesis. Cd79b-mutant murine DLBCL were enriched for IgM surface expression, reminiscent of their human counterparts. Moreover, Cd79b-mutant lymphomas displayed a robust formation of cytoplasmic signaling complexes involving MYD88, CD79B, MALT1, and BTK. These complexes were disrupted upon pharmacological BTK inhibition. The BTK inhibitor-mediated disruption of these signaling complexes translated into a selective ibrutinib sensitivity of lymphomas harboring combined Cd79b and Myd88 mutations. Altogether, this in-depth cross-species comparison provides a framework for the development of molecularly targeted therapeutic intervention strategies in DLBCL.