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An autochthonous mouse model of Myd88- and BCL2-driven diffuse large B-cell lymphoma reveals actionable molecular vulnerabilities

Authors

  • R. Flümann
  • T. Rehkämper
  • P. Nieper
  • P. Pfeiffer
  • A. Holzem
  • S. Klein
  • S. Bhatia
  • M. Kochanek
  • I. Kisis
  • B.W. Pelzer
  • H. Ahlert
  • J. Hauer
  • A. da Palma Guerreiro
  • J.A. Ryan
  • M. Reimann
  • A. Riabinska
  • J. Wiederstein
  • M. Krüger
  • M. Deckert
  • J. Altmüller
  • A.R. Klatt
  • L.P. Frenzel
  • L. Pasqualucci
  • W. Béguelin
  • A.M. Melnick
  • S. Sander
  • M. Montesinos-Rongen
  • A. Brunn
  • P. Lohneis
  • R. Büttner
  • H. Kashkar
  • A. Borkhardt
  • A. Letai
  • T. Persigehl
  • M. Peifer
  • C.A. Schmitt
  • H.C. Reinhardt
  • G. Knittel

Journal

  • Blood Cancer Discovery

Citation

  • Blood Cancer Discov 2 (1): 70-91

Abstract

  • Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in MYD88, as well as BCL2 copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a Myd88 and Bcl2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased PD-L1 expression, compared to GCB-DLBCL. In vivo experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring MYD88 and BCL2 aberrations.


DOI

doi:10.1158/2643-3230.BCD-19-0059