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| Status |
Public on Jun 01, 2021 |
| Title |
Transcriptional profiling of murine germinal center (GC) B cells from GC-specific conditional Crebbp and Ep300 knock-out mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Inactivating mutations of the CREBBP acetyltransferase and, at lower frequencies, its paralogue EP300 are among the most common genetic alterations in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most frequent B cell malignancies. Here we uncover unexpected distinct functions for CREBBP and EP300 in the germinal center (GC), i.e. the target structure for most human B cell lymphomas. We show that these proteins modulate non-overlapping transcriptional programs that are preferentially enriched in biological functions associated with the separate anatomic compartments of the GC. Consistently, deletion of CREBBP or EP300 have opposing effects on GC formation in vivo. Nonetheless, these proteins partially compensate for each other to maintain a minimal threshold of acetyltransferase activity and guarantee homeostatic control of the GC, which is completely abrogated by their combined loss. This synthetic lethal interaction is retained in DLBCL cells, identifying an Achille’s heel in CREBBP-mutant lymphomas that could be pharmacologically targeted by using a novel, selective small molecule inhibitor of the CREBBP/EP300 bromodomain. These data shed light on the unique roles of CREBBP and EP300 in the physiology and pathology of GC B cells, and provide a proof-of-principle for the development and testing of EP300 inhibition as a therapeutic strategy in these diseases.
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| Overall design |
Animals were immunized by intraperitoneal injection of sheep-red-blood-cells to induce T-cell dependent responses, and GC B cells (B220+CD95+PNA+) were sorted 12 days post immunization to extract total RNA for next generation sequencing analysis, as described in detail in the associated manuscript.
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| Contributor(s) |
Pasqualucci L, Holmes AB |
| Citation(s) |
31519498 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA172492 |
Role of KMT2D Gene Inactivation in B cell Non Hodgkin Lymphoma |
Trustees of Columbia University in the City of New York |
Laura Pasqualucci |
| P50 CA192937 |
MSK SPORE in Lymphoma |
Sloan Kettering Institute for Cancer Research |
ANAS YOUNES |
| P50 CA192937 |
MSK SPORE in Lymphoma |
Sloan Kettering Institute for Cancer Research |
ANDREW D. ZELENETZ |
|
| Submission date |
Dec 20, 2018 |
| Last update date |
Jun 01, 2021 |
| Contact name |
Laura Pasqualucci |
| E-mail(s) |
lp171@cumc.columbia.edu
|
| Organization name |
Columbia University
|
| Department |
Institute for Cancer Genetics
|
| Street address |
1130 St Nicholas Avenue
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA510973 |
| SRA |
SRP174041 |
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