| First Author | Flümann R | Year | 2024 |
| Journal | Blood Adv | Volume | 8 |
| Issue | 5 | Pages | 1063-1074 |
| PubMed ID | 38060829 | Mgi Jnum | J:351007 |
| Mgi Id | MGI:7665371 | Doi | 10.1182/bloodadvances.2023011213 |
| Citation | Flumann R, et al. (2024) An inducible Cd79b mutation confers ibrutinib sensitivity in mouse models of Myd88-driven diffuse large B-cell lymphoma. Blood Adv 8(5):1063-1074 |
| abstractText | 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. |
