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@ARTICLE{Flmann:186701,
      author       = {R. Flümann and J. Hansen and B. W. Pelzer and P. Nieper
                      and T. Lohmann and I. Kisis and T. Riet and V. Kohlhas and
                      P.-H. Nguyen and M. Peifer and N. Abedpour and G. Bosco and
                      R. K. Thomas and M. Kochanek and J. Knüfer and L. Jonigkeit
                      and F. Beleggia and A. Holzem and R. Büttner and P. Lohneis
                      and J. Meinel and M. Ortmann and T. Persigehl and M. Hallek
                      and D. P. Calado and M. Chmielewski and L. S. Klein$^*$ and
                      J. R. Göthert$^*$ and B. Chapuy and B. Zevnik and F. T.
                      Wunderlich and B. von Tresckow$^*$ and R. D. Jachimowicz and
                      A. M. Melnick and H. C. Reinhardt$^*$ and G. Knittel$^*$},
      title        = {{D}istinct {G}enetically {D}etermined {O}rigins of
                      {M}yd88/{BCL}2-{D}riven {A}ggressive {L}ymphoma
                      {R}ationalize {T}argeted {T}herapeutic {I}ntervention
                      {S}trategies.},
      journal      = {Blood cancer discovery},
      volume       = {4},
      number       = {1},
      issn         = {2643-3230},
      address      = {Philadelphia, PA},
      publisher    = {American Association for Cancer Research},
      reportid     = {DKFZ-2023-00070},
      pages        = {78 - 97},
      year         = {2023},
      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.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.},
      subtyp        = {Editorial},
      keywords     = {Humans / Mice / Animals / Myeloid Differentiation Factor
                      88: genetics / Myeloid Differentiation Factor 88: metabolism
                      / B-Lymphocytes / Lymphoma, Large B-Cell, Diffuse: genetics
                      / Lymphoma, Large B-Cell, Diffuse: therapy / Plasma Cells:
                      metabolism / Plasma Cells: pathology / Proto-Oncogene
                      Proteins c-bcl-2: genetics / Proto-Oncogene Proteins
                      c-bcl-2: metabolism / Proto-Oncogene Proteins c-bcl-2:
                      therapeutic use / Myeloid Differentiation Factor 88 (NLM
                      Chemicals) / Proto-Oncogene Proteins c-bcl-2 (NLM Chemicals)
                      / BCL2 protein, human (NLM Chemicals) / Myd88 protein, mouse
                      (NLM Chemicals)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36346827},
      pmc          = {pmc:PMC9816818},
      doi          = {10.1158/2643-3230.BCD-22-0007},
      url          = {https://inrepo02.dkfz.de/record/186701},
}