Distinct genetically-determined origins of Myd88/Bcl2-driven aggressive lymphoma rationalize targeted therapeutic intervention strategies.
Ruth FlumannJulia HansenBenedikt W PelzerPascal NieperTim LohmannIlmars KisisTobias RietViktoria KohlhasPhuong-Hien NguyenMartin PeiferNima AbedpourGraziella BoscoRoman K ThomasMoritz KochanekJacqueline KnuferLorenz JonigkeitFilippo BeleggiaAlessandra M E HolzemReinhard ButtnerPhilipp LohneisJorn MeinelMonika OrtmannThorsten PersigehlMichael HallekDinis Pedro CaladoMarkus ChmielewskiSebastian KleinJoachim R GöthertBjoern ChapuyElena I RugarliFrank Thomas WunderlichBastian von TresckowRon D JachimowiczAri M MelnickHans Christian ReinhardtGero KnittelPublished in: Blood cancer discovery (2022)
Genomic profiling revealed the identity of at least 5 subtypes of 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- and mass cytometry analyses to demonstrate that Prdm1- or Spib-altered lymphomas display molecular features consistent with pre-memory 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 out 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 anti-murine-CD19-CAR-T cell therapy, in vivo.
Keyphrases
- cell therapy
- diffuse large b cell lymphoma
- copy number
- single cell
- toll like receptor
- end stage renal disease
- genome wide
- newly diagnosed
- ejection fraction
- randomized controlled trial
- poor prognosis
- stem cells
- chronic kidney disease
- rna seq
- mouse model
- acute lymphoblastic leukemia
- prognostic factors
- mesenchymal stem cells
- gene expression
- peritoneal dialysis
- hodgkin lymphoma
- cancer therapy
- tyrosine kinase
- transcription factor
- long non coding rna
- inflammatory response
- binding protein
- bone marrow