microRNA-dependent modulation of histone acetylation in Waldenström macroglobulinemia

Aldo M. Roccaro, Antonio Sacco, Xiaoying Jia, Abdel Kareem Azab, Patricia Maiso, Hai T. Ngo, Feda Azab, Judith Runnels, Phong Quang, Irene M. Ghobrial

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77 Scopus citations

Abstract

Waldenström macroglobulinemia (WM) cells present with increased expression of microRNA-206 (miRNA-206) and reduced expression of miRNA-9*. Predicted miRNA-206- and -9*-targeted genes include histone deacetylases (HDACs) and histone acetyl transferases (HATs), indicating that these miRNAs may play a role in regulating histone acetylation.We were able to demonstrate that primary WM cells are characterized by unbalanced expression of HDACs and HATs, responsible for decreased acetylated histone-H3 and -H4, and increased HDAC activity. We next examined whether miRNA-206 and -9* modulate the aberrant expression of HDAC and HATs in WM cells leading to increased transcriptional activity. We found that restoring miRNA-9* levels induced toxicity in WM cells, supported by down-modulation of HDAC4 and HDAC5 and up-regulation of acetyl-histone-H3 and -H4. These, together with inhibited HDAC activity, led to induction of apoptosis and autophagy in WM cells. To further confirm that miRNA-9*-dependent modulation of histone acetylation is responsible for induction of WM cytotoxicity, a novel class of HDAC inhibitor (LBH589) was used; we confirmed that inhibition of HDAC activity leads to toxicity in this disease. These findings confirm that histone-modifying genes and HDAC activity are deregulated in WM cells, partially driven by the aberrant expression of miRNA-206 and -9* in the tumor clone.

Original languageEnglish
Pages (from-to)1506-1514
Number of pages9
JournalBlood
Volume116
Issue number9
DOIs
StatePublished - Sep 2 2010
Externally publishedYes

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    Roccaro, A. M., Sacco, A., Jia, X., Azab, A. K., Maiso, P., Ngo, H. T., Azab, F., Runnels, J., Quang, P., & Ghobrial, I. M. (2010). microRNA-dependent modulation of histone acetylation in Waldenström macroglobulinemia. Blood, 116(9), 1506-1514. https://doi.org/10.1182/blood-2010-01-265686