Distinct Genetically Determined Origins of <i>Myd88</i>/<i>BCL2</i>-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies-Reference-Cited by-同舟云学术

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

Published:2022-11-07 Issue:1 Volume:4 Page:78-97
ISSN:2643-3230
Container-title:Blood Cancer Discovery
language:en
Short-container-title:

Author:

Flümann Ruth¹²³⁴⁵^ORCID,Hansen Julia⁵^ORCID,Pelzer Benedikt W.¹⁴⁶^ORCID,Nieper Pascal¹²³⁴^ORCID,Lohmann Tim¹²³⁴^ORCID,Kisis Ilmars¹²³⁴⁷^ORCID,Riet Tobias¹²^ORCID,Kohlhas Viktoria¹²³^ORCID,Nguyen Phuong-Hien¹²³^ORCID,Peifer Martin²⁷^ORCID,Abedpour Nima²⁷^ORCID,Bosco Graziella⁷^ORCID,Thomas Roman K.⁷^ORCID,Kochanek Moritz¹^ORCID,Knüfer Jacqueline¹,Jonigkeit Lorenz¹^ORCID,Beleggia Filippo¹²³⁴⁷^ORCID,Holzem Alessandra¹²³⁴^ORCID,Büttner Reinhard⁸^ORCID,Lohneis Philipp⁸^ORCID,Meinel Jörn⁸^ORCID,Ortmann Monika⁸,Persigehl Thorsten⁹^ORCID,Hallek Michael¹²³⁴^ORCID,Calado Dinis Pedro¹⁰^ORCID,Chmielewski Markus¹²^ORCID,Klein Sebastian¹¹^ORCID,Göthert Joachim R.¹¹^ORCID,Chapuy Bjoern¹²^ORCID,Zevnik Branko²^ORCID,Wunderlich F. Thomas¹³^ORCID,von Tresckow Bastian¹¹^ORCID,Jachimowicz Ron D.¹²³⁴⁵^ORCID,Melnick Ari M.⁶^ORCID,Reinhardt Hans Christian¹¹^ORCID,Knittel Gero¹¹^ORCID

Affiliation:

1. 1Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

2. 2Center for Molecular Medicine, University of Cologne, Cologne, Germany.

3. 3Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

4. 4Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

5. 5Max Planck Institute for Biology of Ageing, Cologne, Germany.

6. 6Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, New York.

7. 7Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

8. 8Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

9. 9Department of Radiology and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

10. 10The Francis Crick Institute, London, United Kingdom.

11. 11Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, West German Cancer Center, German Cancer Consortium (DKTK partner site Essen), Center for Molecular Biotechnology, Essen, Germany.

12. 12Department of Hematology, Oncology and Tumorimmunology, Charité, University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany.

13. 13Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany.

Abstract

Abstract Genomic profiling 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–specific Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole-exome sequencing, transcriptome, flow-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 five 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 biology of MYD88-driven human DLBCL. These models revealed robust preclinical activity of combined BTK/BCL2 inhibition. We confirmed activity of this regimen in pretreated non–GCB-DLBCL patients. See related commentary by Leveille et al., p. 8. This article is highlighted in the In This Issue feature, p. 1

Funder

German-Israeli Foundation for Scientific Research and Development

Deutsche Forschungsgemeinschaft

Deutsche Jose Carreras Leukämie-Stiftung

Else Kröner-Fresenius-Stiftung

Deutsche Krebshilfe

Dr. Mildred Scheel Stiftung für Krebsforschung

Bundesministerium für Bildung und Forschung

Publisher

American Association for Cancer Research (AACR)

Subject

General Medicine