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Series GSE67494 Query DataSets for GSE67494
Status Public on Sep 10, 2015
Title Identification of KMT2D regulated genes in germinal center B cells
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Somatic mutations of the KMT2D methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), these mutations are highly recurrent and occur early during tumorigenesis, suggesting a central role in transformation. Here we show that FL/DLBCL-associated KMT2D mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in germinal center (GC) B cells and DLBCL, consistent with the enrichment of KMT2D binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, leads to an increase in GC B cells, whose transcriptional profile is enriched in cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Kmt2d-deficient B cells exhibit proliferative advantage ex vivo. Loss of Kmt2d combined with BCL2 deregulation, mimicking FL/DLBCL pathogenesis, leads to an increased incidence of clonal lymphoproliferations resembling the features of the human tumors. These findings suggest that early KMT2D loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events.
Overall design ChIP-seq analysis of KMT2D bound regions and histone methylation (H3K4me3, H3K4me1) in normal human germinal center B cells.
Contributor(s) Pasqualucci L, Holmes AB, Basso K, Dalla-Favera R
Citation(s) 26366712
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
Submission date Apr 01, 2015
Last update date Feb 23, 2023
Contact name Laura Pasqualucci
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
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (10)
GSM1648033 CB4_H3K4me1
GSM1648034 CB4_H3K4me3
GSM1648035 CB4_MLL2
BioProject PRJNA280081
SRA SRP056786

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Supplementary file Size Download File type/resource
GSE67494_RAW.tar 2.3 Mb (http)(custom) TAR (of BEDGRAPH)
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Raw data are available in SRA
Processed data provided as supplementary file

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