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An Inducible Cd79b Mutation Confers Ibrutinib Sensitivity in Mouse Models of Myd88-driven Diffuse Large B-cell Lymphoma.

BLOOD ADVANCES(2024)

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摘要
Diffuse large B -cell lymphoma (DLBCL) is the most common aggressive lymphoma and constitutes a highly heterogenous disease. Recent comprehensive genomic pro filing revealed the identity of numerous molecularly de fined 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 speci fically 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.
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关键词
Germany,B -cell receptor
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