Rbm15-Mkl1 interacts with the Setd1b histone H3-Lys4 methyltransferase via a SPOC domain that is required for cytokine-independent proliferation

Jeong Heon Lee, David G. Skalnik

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The Rbm15-Mkl1 fusion protein is associated with acute megakaryoblastic leukemia (AMKL), although little is known regarding the molecular mechanism(s) whereby this fusion protein contributes to leukemogenesis. Here, we show that both Rbm15 and the leukemogenic Rbm15-Mkl1 fusion protein interact with the Setd1b histone H3-Lys4 methyltransferase (also known as KMT2G). This interaction is direct and requires the Rbm15 SPOC domain and the Setd1b LSD motif. Over-expression of Rbm15-Mkl1 in the 6133 megakaryoblastic leukemia cell line, previously established by expression of the Rbm15-Mkl1 fusion protein in mice (Mercher et al., [2009] J. Clin. Invest. 119, 852-864), leads to decreased levels of endogenous Rbm15 and increased levels of endogenous Mkl1. These cells exhibit enhanced proliferation and cytokine-independent cell growth, which requires an intact Rbm15 SPOC domain that mediates interaction between the Rbm15-Mkl1 fusion protein and the Setd1b methyltransferase. These results reveal altered Setd1b complex function and consequent altered epigenetic regulation as a possible molecular mechanism that mediates the leukemogenic activity of the Rbm15-Mkl1 fusion protein in AMKL.

Original languageEnglish (US)
Article numbere42965
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 21 2012
Externally publishedYes

Fingerprint

methyltransferases
Methyltransferases
histones
Histones
cytokines
Fusion reactions
Cytokines
Leukemia, Megakaryoblastic, Acute
leukemia
Proteins
proteins
Protein Methyltransferases
Lysergic Acid Diethylamide
Epigenomics
Cell growth
Leukemia
epigenetics
histone methyltransferase
cell growth
Cell Line

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Rbm15-Mkl1 interacts with the Setd1b histone H3-Lys4 methyltransferase via a SPOC domain that is required for cytokine-independent proliferation. / Lee, Jeong Heon; Skalnik, David G.

In: PLoS One, Vol. 7, No. 8, e42965, 21.08.2012.

Research output: Contribution to journalArticle

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