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PMID: 22927943 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

PloS one ·Vol. 7 ·No. 8 ·2012-00-00 ·Pages e42965

Lee JH, Skalnik DG

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.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Animals Cell Line, Tumor Cell Proliferation Cell Survival Cell Transformation, Neoplastic DNA-Binding Proteins/metabolism Gene Expression Regulation HEK293 Cells Histone-Lysine N-Methyltransferase/chemistry,metabolism Humans Mice Molecular Sequence Data Oncogene Proteins, Fusion/metabolism Protein Binding Protein Structure, Tertiary RNA-Binding Proteins/chemistry,metabolism Trans-Activators
Chemicals
DNA-Binding Proteins MRTFA protein, human Oncogene Proteins, Fusion RBM15 protein, human RNA-Binding Proteins Rbm15 protein, mouse Trans-Activators Histone-Lysine N-Methyltransferase
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Lee Jeong-Heon
Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America. jeonglee@iupui.edu
Skalnik David G
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0042965
Email
jeonglee@iupui.edu
Published
2012-00-00
Epub
2012-00-21
Pages
e42965
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3424240
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0042965 PMC Full Text View journal details
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