Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia

Shih Shih Chen, Aparna Raval, Amy J. Johnson, Erin Hertlein, Te Hui Liua, Victor X. Jin, Mara H. Sherman, Shu Jun Liu, David W. Dawson, Katie E. Williams, Mark Lanasa, Sandya Liyanarachchi, Thomas S. Lin, Guido Marcucci, Yuri Pekarsky, Ramana Davuluri, Carlo M. Croce, Denis C. Guttridge, Michael A. Teitell, John C. ByrdChristoph Plass

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the Eμ-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from Eμ-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of Foxd3 expression due to an NF-κB p50/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-κB components in CLL and potentially other B-cell malignancies.

Original languageEnglish (US)
Pages (from-to)13433-13438
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number32
DOIs
StatePublished - Aug 11 2009
Externally publishedYes

Keywords

  • CLL
  • DNA methylation
  • Epigenetics
  • FOXD3

ASJC Scopus subject areas

  • General

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  • Cite this

    Chen, S. S., Raval, A., Johnson, A. J., Hertlein, E., Liua, T. H., Jin, V. X., Sherman, M. H., Liu, S. J., Dawson, D. W., Williams, K. E., Lanasa, M., Liyanarachchi, S., Lin, T. S., Marcucci, G., Pekarsky, Y., Davuluri, R., Croce, C. M., Guttridge, D. C., Teitell, M. A., ... Plass, C. (2009). Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America, 106(32), 13433-13438. https://doi.org/10.1073/pnas.0906455106