TitleGenomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma.
Publication TypeJournal Article
Year of Publication2010
AuthorsLeshchenko, Violetta V., Kuo Pei-Yu, Shaknovich Rita, Yang David T., Gellen Tobias, Petrich Adam, Yu Yiting, Remache Yvonne, Weniger Marc A., Rafiq Sarwish, K Suh Stephen, Goy Andre, Wilson Wyndham, Verma Amit, Braunschweig Ira, Muthusamy Natarajan, Kahl Brad S., Byrd John C., Wiestner Adrian, Melnick Ari, and Parekh Samir
Date Published2010 Aug 19
KeywordsAntigens, CD, Antigens, Neoplasm, Biomarkers, Tumor, Cell Proliferation, Cells, Cultured, DNA Methylation, Drug Design, Drug Discovery, Fluorescent Antibody Technique, Gene Expression Profiling, Genome, Human, Humans, Immunoenzyme Techniques, Lymphoma, Mantle-Cell, Oligonucleotide Array Sequence Analysis, Tetraspanins

<p>Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of 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 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 histone deacetylase inhibitor suberoylanilide hydroxamic acid in induction of the hypermethylated genes and anti-MCL cytotoxicity. Our data show prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.</p>

Alternate JournalBlood
PubMed ID20427703
PubMed Central IDPMC2938124
Grant ListP01 CA95426 / CA / NCI NIH HHS / United States
P01 CA813534 / CA / NCI NIH HHS / United States
R01 HL082946 / HL / NHLBI NIH HHS / United States
K12 CA132783-01 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States
P01 CA095426 / CA / NCI NIH HHS / United States
K12 CA132783 / CA / NCI NIH HHS / United States