Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia

Deepa Sampath, Chaomei Liu, Karthik Vasan, Melanie Sulda, Vinay Puduvalli, William Wierda, Michael Keating

    Research output: Contribution to journalArticle

    137 Citations (Scopus)

    Abstract

    Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition-induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor-based therapy.

    Original languageEnglish
    Pages (from-to)1162-1172
    Number of pages11
    JournalBlood
    Volume119
    Issue number5
    DOIs
    Publication statusPublished - 2012

    Fingerprint Dive into the research topics of 'Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia'. Together they form a unique fingerprint.

  • Cite this

    Sampath, D., Liu, C., Vasan, K., Sulda, M., Puduvalli, V., Wierda, W., & Keating, M. (2012). Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. Blood, 119(5), 1162-1172. https://doi.org/10.1182/blood-2011-05-351510