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| Status |
Public on Jul 31, 2010 |
| Title |
Genome-wide DNA Methylation Analysis Reveals Novel Targets for Drug Development in Mantle Cell Lymphoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
Methylation profiling by genome tiling array
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| Summary |
Mantle Cell Lymphoma (MCL) is a mostly incurable malignancy arising from naïve B cells (NBC) in the mantle zone of lymph node follicles. We analyzed genome-wide methylation in MCL patients using the HELP (Hpa II tiny fragment Enrichment by Ligation mediated PCR) assay and found significant aberrancy in promoter methylation patterns as compared to normal NBCs. Using biological and stringent statistical criteria, we further identified four hypermethylated genes CDKN2B, MLF-1, PCDH8, HOXD8 and four hypomethylated genes CD37, HDAC1, NOTCH1 and CDK5 where aberrant methylation was associated with inverse changes in mRNA levels. MassArray Epityper analysis confirmed the presence of differential methylation at the promoter region of these genes. Immunohistochemical analysis of an independent cohort of 14 MCL patient samples, confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a novel small modular immunopharmaceutical(CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the HDAC inhibitor SAHA in induction of the four hypermethylated genes CDKN2B, MLF-1, PCDH8 and HOXD8. The combination of Decitabine and SAHA also resulted in potent and synergistic anti-MCL cytotoxicity as compared to either drug alone. In conclusion, our analysis shows prominent and aberrant methylation of the MCL genome and identifies novel differentially methylated and expressed genes in MCL cell lines and patient samples. Furthermore, our data suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.
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| Overall design |
Gene expression profiling by array comprised of 8 mantle cell lymphoma (MCL) cell lines and 8 leukemic blast from blood from patients newly diagnosed with MCL. Unbiased genome-wide analysis of DNA methylation in leukemic blast from peripheral blood or pheresis products from 22 patients newly diagnosed with mantle cell lymphoma (MCL) prior to any treatment. 10 IgD+ Na ve B cells from specimens from healthy donors undergoing routine tonsillectomy were used as appropriate controls. Methylation patterns of 13 MCL cell lines were also compared.
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| Contributor(s) |
Leshchenko V, Kuo P, Shaknovich R, Yang DT, Gellen T, Remache Y, Weniger M, Rafiq S, Suh S, Goy A, Wilson W, Verma A, Muthusamy N, Kahl B, Byrd J, Wiestner A, Melnick A, Parekh S |
| Citation(s) |
20427703 |
| Submission date |
Dec 01, 2009 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Samir Parekh |
| E-mail(s) |
sparekh@aecom.yu.edu
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| Phone |
(718) 430-4136
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| Organization name |
Albert Einstein College of Medicine
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| Department |
Cancer center
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| Street address |
1300 Morris Park Ave
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| City |
Bronx |
| State/province |
NY |
| ZIP/Postal code |
10461 |
| Country |
USA |
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| Platforms (3) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
| GPL571 |
[HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array |
| GPL6604 |
HG17_HELP_Promoter |
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| Samples (61)
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| Relations |
| BioProject |
PRJNA120777 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE19243_RAW.tar |
647.3 Mb |
(http)(custom) |
TAR (of CEL, PAIR) |
| Processed data included within Sample table |
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