An inducible Cd79b mutation confers ibrutinib sensitivity in mouse models of Myd88-driven diffuse large B-cell lymphoma

被引：1

作者：

Fluemann, Ruth ^{[1
,2
,3
,4
,5
,6
]}

Hansen, Julia ^{[1
,2
,6
]}

Meinel, Joern ^{[2
,7
]}

Pfeiffer, Pauline ^{[1
,2
]}

Wittkopf, Hannah Goldfarb ^{[1
,2
,6
]}

Luetz, Anna ^{[1
,2
,6
]}

Wirtz, Jessica ^{[1
,2
,6
]}

Moellmann, Michael ^{[8
]}

Zhou, Tanja ^{[8
]}

Tabatabai, Areya ^{[8
]}

Lohmann, Tim ^{[1
,2
]}

Jauch, Maximilian ^{[8
]}

Beleggia, Filippo ^{[1
,2
,5
,9
]}

Pelzer, Benedikt ^{[10
]}

Ullrich, Fabian ^{[8
]}

Hoefmann, Svenja ^{[8
]}

Arora, Aastha ^{[8
]}

Persigehl, Thorsten ^{[2
,11
]}

Buettner, Reinhard ^{[7
]}

von Tresckow, Bastian ^{[8
]}

Klein, Sebastian ^{[8
]}

Jachimowicz, Ron D. ^{[1
,2
,3
,4
,5
,6
]}

Reinhardt, Hans Christian ^{[8
]}

Knittel, Gero ^{[8
]}

机构：

[1] Univ Cologne, Fac Med, Ctr Integrated Oncol Aachen Bonn Cologne Dusseldo, Dept Internal Med 1, Cologne, Germany

[2] Univ Cologne, Univ Hosp Cologne, Cologne, Germany

[3] Univ Cologne, Ctr Mol Med, Cologne, Germany

[4] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[5] Univ Hosp Cologne, Fac Med, Mildred Scheel Sch Oncol Aachen Bonn Cologne Duss, Cologne, Germany

[6] Max Planck Inst Biol Ageing, Cologne, Germany

[7] Univ Cologne, Fac Med, Inst Pathol, Cologne, Germany

[8] Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr,German Canc Consortium Partn, Ctr Mol Biotechnol,Dept Hematol & Stem Cell Trans, Hufelandst 55, D-45147 Essen, Germany

[9] Univ Cologne, Fac Med, Dept Translat Genom, Cologne, Germany

[10] Cornell Univ, Weill Cornell Med, Dept Med, Div Hematol Oncol, New York, NY USA

[11] Univ Cologne, Fac Med, Dept Radiol & Intervent Radiol, Cologne, Germany

来源：

BLOOD ADVANCES | 2024年 / 8卷 / 05期

关键词：

Germany; B -cell receptor; TYROSINE KINASE; CLINICAL-PRACTICE; IG-ALPHA; RITUXIMAB; TRANSPLANTATION; THERAPY; CLASSIFICATION; CHEMOTHERAPY; PATHOGENESIS; EXPRESSION;

D O I：

10.1182/bloodadvances.2023011213

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

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.

引用

页码：1063 / 1074

页数：12

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