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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Feb 19, 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 [RNA-Seq] |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| 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.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for 1) mouse centroblasts (CB) and centrocytes (CC) sorted from sheep red blood cell (SRBC)-immunized genetically engineered mouse models (GEMMs), which include Cg1Cre+/- (WT); Cg1Cre+/-, Crebbp fl/+ (C); Cg1Cre+/-, Kmt2d fl/+ (K); Cg1Cre+/-, Crebbp fl/+, Kmt2d fl/+ (CK); n = 3-4 mice for each genotype. 2) isogenic human GCB-DLBCL OCI-Ly7 cell lines, which include WT, CREBBP-R1446C (C, HAT inactivating point mutation), KMT2D-KO (K), and CREBBP-R1446C + KMT2D-KO (CK); n = 2 biological replicates for each genotype. 3) mouse GC B cells sorted from lymphomagenesis mice at day 235 post-BMT, which include VavP-BCL2+/- (BCL2); VavP-BCL2+/-, Cg1Cre+/-, Crebbp fl/+ (BCL2+C); VavP-BCL2+/-, Cg1Cre+/-, Kmt2d fl/+ (BCL2+K); VavP-BCL2+/-, Cg1Cre+/-, Crebbp fl/+, Kmt2d fl/+ (BCL2+CK); n = 4 mice for each genotype.
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| Contributor(s) |
Chin C, Li J, Béguelin W, Melnick A |
| Citation(s) |
38570506 |
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| Submission date |
Feb 03, 2023 |
| Last update date |
Apr 17, 2024 |
| Contact name |
Christopher Russell Chin |
| E-mail(s) |
chc2077@med.cornell.edu
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| Phone |
3393640514
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| Organization name |
Weill Cornell
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| Lab |
Melnick Lab
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| Street address |
413 E 69th Street, Belfer Building, BB-1462
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| City |
New York City |
| State/province |
NY |
| ZIP/Postal code |
10021 |
| Country |
USA |
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| Platforms (2) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (53)
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| 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. |
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| Relations |
| BioProject |
PRJNA931290 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE224465_ck_bcl2_gcb_featurecounts.merged.counts.tsv.gz |
747.6 Kb |
(ftp)(http) |
TSV |
| GSE224465_ck_sorted_gcb_rna_featurecounts.merged.counts.tsv.gz |
1.5 Mb |
(ftp)(http) |
TSV |
| GSE224465_ly7_featurecounts.merged.counts.tsv.gz |
895.7 Kb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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