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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3145-3154.
Prepublished online as a Blood First Edition Paper on December 21, 2007; DOI 10.1182/blood-2007-06-092122.
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Submitted June 4, 2007
Accepted December 6, 2007
The Multiple Myeloma SET Domain (MMSET) protein is a histone methyltransferase with characteristics of a transcriptional co-repressor
Jotin Marango, Manabu Shimoyama, Hitomi Nishio, Julia A. Meyer, Dong-Joon Min, Andres Sirulnik, Yolanda Martinez-Martinez, Marta Chesi, P. Leif Bergsagel, Ming-Ming Zhou, Samuel Waxman, Boris A. Leibovitch, Martin J. Walsh, and Jonathan D. Licht*
Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY, United States
Division of Hematology/Oncology, Kobe University Graduate School of Medicine, Kobe, Japan
Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, United States
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Robert H. Laurie Comprehensive Cancer Center, Chicago, IL, United States
Division of Hematological Malignancy, Dana-Farber Cancer Institute, Boston, MA, United States
Mayo Clinic, Scottsdale, AZ, United States
Structural Biology Program, Mount Sinai School of Medicine, New York, NY, United States
* Corresponding author; email: j-licht{at}northwestern.edu.
MMSET, identified by its fusion to the IgH locus in t(4;14) associated multiple myeloma, posses domains found within chromatin regulators including the SET domain. MMSET protein is overexpressed and tighly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20; while MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin-embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetyaltion. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a and the histone demethylase LSD1 suggesting that it is a component of co-repressor complexes. Furthemore MMSET co-expression enhances HDAC1 and HDAC2-mediated repression in transcriptional reporter assays. Finally shRNA mediated knockdown of MMSET compromised viability of a myeloma cell line suggesting a biological role for the protein in malignant cell growth. Collectively, these data suggest that by acting directly as a modifier of chromatin as well as through binding of other chromatin modifying enzymes, MMSET-Influences gene expression and potentially acts as a pathogenic agent in multiple myeloma.
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