Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies

被引：8

作者：

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

Hansen, Julia ^{[6
]}

Pelzer, Benedikt W. ^{[1
,2
,5
,7
]}

Nieper, Pascal ^{[1
,2
,3
,4
,5
]}

Lohmann, Tim ^{[1
,2
,3
,4
,5
]}

Kisis, Ilmars ^{[1
,2
,3
,4
,5
,8
]}

Riet, Tobias ^{[1
,2
,3
]}

Kohlhas, Viktoria ^{[1
,2
,3
,4
]}

Phuong-Hien Nguyen ^{[1
,2
,3
,4
]}

Peifer, Martin ^{[2
,3
,8
]}

Abedpour, Nima ^{[2
,3
,8
]}

Bosco, Graziella ^{[2
,8
]}

Thomas, Roman K. ^{[2
,8
]}

Kochanek, Moritz ^{[1
,2
]}

Knufer, Jacqueline ^{[1
,2
]}

Jonigkeit, Lorenz ^{[1
,2
]}

Beleggia, Filippo ^{[1
,2
,3
,4
,5
,8
]}

Holzem, Alessandra ^{[1
,2
,3
,4
,5
]}

Buttner, Reinhard ^{[2
,9
]}

Lohneis, Philipp ^{[2
,9
]}

Meinel, Jorn ^{[2
,9
]}

Ortmann, Monika ^{[2
,9
]}

Persigehl, Thorsten ^{[10
,11
]}

Hallek, Michael ^{[1
,2
,3
,4
,5
]}

Calado, Dinis Pedro ^{[12
]}

Chmielewski, Markus ^{[1
,2
,3
]}

Klein, Sebastian ^{[13
]}

Goethert, Joachim R. ^{[13
]}

Chapuy, Bjoern ^{[14
]}

Zevnik, Branko ^{[3
]}

Wunderlich, F. Thomas ^{[15
]}

von Tresckow, Bastian ^{[13
]}

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

Melnick, Ari M. ^{[7
]}

Reinhardt, Hans Christian ^{[13
]}

Knittel, Gero ^{[13
]}

机构：

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

[2] 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 Cologne, Fac Med, Mildred Scheel Sch Oncol, Aachen Bonn Cologne Dusseldorf, Cologne, Germany

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

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

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

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

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

[11] Univ Cologne, Univ Hosp Cologne, Cologne, Germany

[12] Francis Crick Inst, London, England

[13] Univ Duisburg Essen, Univ Hosp Essen,German Canc Consortium DKTK Partn, West German Canc Ctr,Dept Hematol & Stem Cell Tra, Ctr Mol Biotechnol,German Canc Consortium DKTK Pa, Essen, Germany

[14] Charite Univ Med Ctr Berlin, Dept Hematol Oncol & Tumorimmunol, Campus Benjamin Franklin, Berlin, Germany

[15] Max Planck Inst Metab Res, Dept Neuronal Control Metab, Cologne, Germany

来源：

BLOOD CANCER DISCOVERY | 2023年 / 4卷 / 01期

关键词：

B-CELL LYMPHOMA; PLASMABLASTIC LYMPHOMA; CLINICAL-PRACTICE; GERMINAL-CENTERS; ETS PROTEIN; T-CELLS; SPI-B; RECEPTOR; TRANSPLANTATION; RITUXIMAB;

D O I：

10.1158/2643-3230.BCD-22-0007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Genomic profi ling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1, and/or SPIB. We generated mouse models harboring B cell-specifi c Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole-exome sequencing, transcriptome, fl ow-cytometry, and mass cytometry analyses to demonstrate that Prdm1- or Spib-altered lymphomas display molecular features consistent with prememory B cells and light-zone B cells, whereas lymphomas lacking these alterations were enriched for late light-zone and plasmablast-associated gene sets. Consistent with the phenotypic evidence for increased B cell receptor signaling activity in Prdm1-altered lymphomas, we demonstrate that combined BTK/BCL2 inhibition displays therapeutic activity in mice and in fi ve of six relapsed/refractory DLBCL patients. Moreover, Prdm1-altered lymphomas were immunogenic upon transplantation into immuno-competent hosts, displayed an actionable PD-L1 surface expression, and were sensitive to antimurine-CD19-CAR-T cell therapy, in vivo. SIGNIFICANCE: Relapsed/refractory DLBCL remains a major medical challenge, and most of these patients succumb to their disease. Here, we generated mouse models, faithfully recapitulating the biol-ogy of MYD88-driven human DLBCL. These models revealed robust preclinical activity of combined BTK/BCL2 inhibition. We confi rmed activity of this regimen in pretreated non-GCB-DLBCL patients.

引用

页码：78 / 97

页数：20

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