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| 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.
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| Overall design |
ChIP-seq analysis of KMT2D bound regions and histone methylation (H3K4me3, H3K4me1) in normal human germinal center B cells.
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| 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 |
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| |
| Submission date |
Apr 01, 2015 |
| Last update date |
Feb 23, 2023 |
| 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) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA280081 |
| SRA |
SRP056786 |
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