NCBI Logo
GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
          Go
Series GSE141452 Query DataSets for GSE141452
Status Public on Dec 07, 2020
Title DLBCL-reminiscent MyD88- or CARD11-mutant aggressive B-cell lymphomas exhibit strong pro-senescent and immune-evasive phenotypes [part1]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Aberrant B-cell receptor (BCR)/NF-kB signaling activity is a prominent feature of diffuse large B-cell lymphoma (DLBCL), particularly of, but not restricted to the activated B-cell (ABC) subtype. Recurrent mutations in this cascade, e.g. in CD79B, CARD11, A20/TNFAIP3 or NFKBIZ, but also in the Toll-like receptor (TLR) pathway transducer MyD88, all converge at NF-kB deregulation, but their differential impact on lymphoma development and biology remains to be dissected. Recapitulating oncogenic myc rearrangements as another common feature of DLBCL, we functionally investigate here primary mouse lymphomas that formed after propagation of Eµ-myc transgenic hematopoietic stem cells (HSC), stably transduced with naturally occurring DLBCL-derived NF-kB mutants, in recipient mice. While most mutants tested supported Myc-driven lymphoma formation through repressed apoptosis, selectively deregulated CARD11- or MyD88-mutant lymphoma cells presented with a macrophage-activating secretion profile, which, in turn, enforced TGF-b-mediated feedback senescence in the lymphoma cell compartment. Moreover, MyD88- or CARD11-mutant Eµ-myc lymphomas – mirrored by matching signatures in their mutant DLBCL counterparts – exhibited high-level expression of the immune checkpoint mediator PD-L1, thus preventing their efficient clearance by adaptive host cell immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-PD1 immune checkpoint blockade, leading to the direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Our functional, cross-species interrogation of a syngeneic and fully immune-competent, BCR/NF-kB-deregulated and DLBCL-reminiscent in vivo-model platform unveils common principles and therapeutic vulnerabilities related to human DLBCL subsets that will inform future personalized treatment strategies.
 
Overall design mRNA profiles of Eµ-myc mouse lymphoma cells isolated from lethally irradiated C57BL/6N mice transplanted with Eµ-myc HSC (hematopoetic stem cells) retrovirally transduced with either MYD88-L265P;sh-scrambled MSCV-GFP or MyD88-L265P;sh-PDL1 MSCV-GFP. SMART-Seq® v4 Ultra® Low Input RNA Kit (Takara) and Nextera XT Kit (Illumina) followed by sequencing with 50 bp single-end reads on HiSeq 2000.
 
Contributor(s) Schmitt CA, Schrezenmeier J, Reimann M, Dolnik A
Citation(s) 33232972
Submission date Dec 04, 2019
Last update date Dec 07, 2020
Contact name Anna Dolnik
E-mail(s) anna.dolnik@charite.de
Organization name Charité Universitätsmedizin Berlin
Department Campus Virchow-Klinikum (CVK)
Lab Hämatologie, Onkologie und Tumorimmunologie
Street address Augustenburger Platz 1
City Berlin
ZIP/Postal code 13353
Country Germany
 
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (12)
GSM4203316 AS-336709-LR-42260
GSM4203317 AS-336708-LR-42260
GSM4203318 AS-336705-LR-42261
This SubSeries is part of SuperSeries:
GSE141454 DLBCL-reminiscent MyD88- or CARD11-mutant aggressive B-cell lymphomas exhibit strong pro-senescent and immune-evasive phenotypes
Relations
BioProject PRJNA593522
SRA SRP234709

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE141452_DESeq2_condition_all_countsNormalized.txt.gz 1.4 Mb (ftp)(http) TXT
GSE141452_DESeq2_condition_all_countsNormalizedTransformed.txt.gz 2.2 Mb (ftp)(http) TXT
GSE141452_RAW.tar 2.2 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap