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SRX23831496: GSM8124857: day235_BCL2+K_rep2; Mus musculus; OTHER
1 ILLUMINA (Illumina NovaSeq 6000) run: 32.5M spots, 6.6G bases, 1.9Gb downloads

External Id: GSM8124857_r1
Submitted by: Melnick Lab, Weill Cornell
Study: 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 [WES]
show Abstracthide Abstract
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: Whole exome 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)
Sample: day235_BCL2+K_rep2
SAMN40255156 • SRS20653253 • All experiments • All runs
Organism: Mus musculus
Library:
Name: GSM8124857
Instrument: Illumina NovaSeq 6000
Strategy: OTHER
Source: GENOMIC
Selection: other
Layout: PAIRED
Construction protocol: Genomic DNA was extracted using the PureLink genomic DNA mini kit (Invitrogen, cat# K182002) following the manual. Sequencing libraries were generated using the Agilent SureSelectXT Mouse All Exon kit (cat# 5190-4641) following the manual.
Runs: 1 run, 32.5M spots, 6.6G bases, 1.9Gb
Run# of Spots# of BasesSizePublished
SRR2821944632,485,2216.6G1.9Gb2024-03-05

ID:
32133293

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