 |
 |
GEO help: Mouse over screen elements for information. |
|
| 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 [part2] |
| 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. Specifically, for the shown FLC transplantation experiments, 8-12 week-old female C57BL/6N recipient mice (Charles River Laboratories) received a single, myelo-ablative dose of 9 Gy total-body gamma-irradiation. After in vitro-transduction of FLC, 10% GFP-positive Sca1+; c-Kit+; lin- cells with the indictaed transgenic and/or knock out genotypes were transplanted via tail vein injection into irradiated mice, which were subsequently monitored until a well-palpable lymphadenopathy had formed. Retroviral vectors used in this experiment were the MSCV 2.2 derived constructs
|
| |
|
| Overall design |
mRNA profiles of manifest Eµ-myc mouse lymphoma cells (mouse strain C57BL/6N ) transduced either with retroviral MSCV vector co-expressing green fluorescent protein (GFP) for control group, or retroviral MSCV-GFP vector with following mutants: CARD11-L251P or CD79B-Y195H or MYD88-L265P; or retroviral MSCV-GFP vector with NFKBIZ or PD-L1 for overexpression. 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 (38)
|
|
| 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 |
PRJNA593523 |
| SRA |
SRP234708 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE141453_RAW.tar |
7.0 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...