Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma

Kelly A. Cycon, Kathleen Mulvaney, Lisa M Rimsza, Daniel Persky, Shawn P. Murphy

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Summary: Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin's lymphoma (NHL) diagnosed in the USA, consists of at least two distinct subtypes: germinal centre B (GCB) and activated B-cell (ABC). Decreased MHC class II (MHCII) expression on the tumours in both DLBCL subtypes directly correlates with significant decreases in patient survival. One common mechanism accounting for MHCII down-regulation in DLBCL is reduced expression of the MHC class II transactivator (CIITA), the master regulator of MHCII transcription. Furthermore, reduced CIITA expression in ABC DLBCL correlates with the presence of the transcriptional repressor positive regulatory domain-I-binding factor-1 (PRDI-BF1). However, the mechanisms underlying down-regulation of CIITA in GCB DLBCL are currently unclear. In this study, we demonstrate that neither PRDI-BF1 nor CpG hypermethylation at the CIITA promoters are responsible for decreased CIITA in GCB DLBCL. In contrast, histone modifications associated with an open chromatin conformation and active transcription were significantly lower at the CIITA promoters in CIITA- GCB cells compared with CIITA+ B cells, which suggests that epigenetic mechanisms contribute to repression of CIITA transcription. Treatment of CIITA- or CIITAlow GCB cells with several different histone deacetylase inhibitors (HDACi) activated modest CIITA and MHCII expression. However, CIITA and MHCII levels were significantly higher in these cells after exposure to the HDAC-1-specific inhibitor MS-275. These results suggest that CIITA transcription is repressed in GCB DLBCL cells through epigenetic mechanisms involving HDACs, and that HDACi treatment can alleviate repression. These observations may have important implications for patient therapy.

Original languageEnglish (US)
Pages (from-to)259-272
Number of pages14
JournalImmunology
Volume140
Issue number2
DOIs
StatePublished - Oct 2013

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Histone Deacetylase Inhibitors
Lymphoma, Large B-Cell, Diffuse
Histocompatibility Antigens Class II
Germinal Center
B-Lymphocytes
Epigenomics
MHC class II transactivator protein
Down-Regulation
Histone Code
Non-Hodgkin's Lymphoma
Chromatin
Therapeutics

Keywords

  • B cells
  • Histone deacetylase inhibitor
  • Human
  • Lymphoma
  • MHC

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma. / Cycon, Kelly A.; Mulvaney, Kathleen; Rimsza, Lisa M; Persky, Daniel; Murphy, Shawn P.

In: Immunology, Vol. 140, No. 2, 10.2013, p. 259-272.

Research output: Contribution to journalArticle

Cycon, Kelly A. ; Mulvaney, Kathleen ; Rimsza, Lisa M ; Persky, Daniel ; Murphy, Shawn P. / Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma. In: Immunology. 2013 ; Vol. 140, No. 2. pp. 259-272.
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