Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma

Violetta V. Leshchenko, Pei Yu Kuo, Rita Shaknovich, David T. Yang, Tobias Gellen, Adam Petrich, Yiting Yu, Yvonne Remache, Marc A. Weniger, Sarwish Rafiq, K. Stephen Suh, Andre Goy, Wyndham Wilson, Amit Verma, Ira Braunschweig, Natarajan Muthusamy, Brad S. Kahl, John C. Byrd, Adrian Wiestner, Ari MelnickSamir Parekh

Research output: Contribution to journalReview article

102 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1025-1034
Number of pages10
JournalBlood
Volume116
Issue number7
DOIs
StatePublished - Aug 19 2010

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Leshchenko, V. V., Kuo, P. Y., Shaknovich, R., Yang, D. T., Gellen, T., Petrich, A., Yu, Y., Remache, Y., Weniger, M. A., Rafiq, S., Suh, K. S., Goy, A., Wilson, W., Verma, A., Braunschweig, I., Muthusamy, N., Kahl, B. S., Byrd, J. C., Wiestner, A., ... Parekh, S. (2010). Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood, 116(7), 1025-1034. https://doi.org/10.1182/blood-2009-12-257485