The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells

Eva Martinez-Garcia, Relja Popovic, Dong Joon Min, Steve M.M. Sweet, Paul M. Thomas, Leonid Zamdborg, Aaron Heffner, Christine Will, Laurence Lamy, Louis M. Staudt, David L. Levens, Neil L. Kelleher, Jonathan D. Licht

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

The multiple myeloma SET domain (MMSET) protein is overexpressed in multiple myeloma (MM) patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/Wolf-Hirschhorn syndrome candidate 1 in development, its mode of action in the pathogenesis of MM is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth, and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation, and integrin signaling. Regulation of many of these genes required functional histone methyltransferase activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM.

Original languageEnglish (US)
Pages (from-to)211-220
Number of pages10
JournalBlood
Volume117
Issue number1
DOIs
StatePublished - Jan 6 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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