|
| Status |
Public on Mar 05, 2024 |
| Title |
Cooperative super-enhancer inactivation caused by heterozygous loss of CREBBP and KMT2D skews B-cell fate decisions and accelerates development of T-cell depleted lymphomas [CapIG-seq] |
| Organism |
Mus musculus |
| Experiment type |
Other
|
| Summary |
Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
|
| |
|
| Overall design |
CapIG-seq (aka, B cell receptor sequencing) for splenic germinal center B cells sorted from lymphoma-bearing mice at day 235 post bone marrow transplant. We sequenced 4 mice replicates for each genotype (i.e., BCL2, BCL2+C, BCL2+K, BCL2+CK)
|
| |
|
| Contributor(s) |
Chin C, Li J, Béguelin W, Melnick A |
| Citation(s) |
38570506 |
| |
| Submission date |
Mar 04, 2024 |
| Last update date |
Apr 17, 2024 |
| Contact name |
Christopher Russell Chin |
| E-mail(s) |
chc2077@med.cornell.edu
|
| Phone |
3393640514
|
| Organization name |
Weill Cornell
|
| Lab |
Melnick Lab
|
| Street address |
413 E 69th Street, Belfer Building, BB-1462
|
| City |
New York City |
| State/province |
NY |
| ZIP/Postal code |
10021 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (16)
|
|
| This SubSeries is part of SuperSeries: |
| GSE224513 |
Cooperative super-enhancer inactivation caused by heterozygous loss of CREBBP and KMT2D skews B-cell fate decisions and accelerates development of T-cell depleted lymphomas. |
|
| Relations |
| BioProject |
PRJNA1083546 |
Less...
More...