Multiple myeloma (MM) represents the malignant transformation of plasma cells, differentiated, post-germinal center B-cells adapted for the production of large quantities of antibody. Multiple myeloma is one of the commonest hematological malignancies and despite the advent of several new therapies such as proteosome inhibitors and thalidomide and the use of stem cell transplant consolidation, the disease is incurable with a median survival of about three years. The pathogenesis of this disease for many years was quite obscure, but over the past decade progress has been made based upon the characterization of consistent chromosomal translocations involving the immunoglobulin heavy chain (IgH). These translocations implicate particular genes in the pathogenesis of myeloma. MMSET (MULTIPLE MYELOMA SET DOMAIN) gene was identified at the breakpoint of the t(4;14) translocation, present in ~15% of multiple myeloma. This gene rearrangement leads to the transcriptional activation and overexpression of the FGFR3 gene and the MMSET gene, however in about 15% of cases only MMSET and not FGFR3 is overexpressed due to the rearrangement leading to the idea that deregulation of MMSET expression is central to the pathogenesis of this form of multiple myeloma. MMSET has a SET domain previously identified in histone methyl transferases and several other protein domains found in chromatin regulators. It has been confirmed that the MMSET protein is significantly overexpressed in myeloma cells harboring the t(4;14) translocation. The preliminary data indicates that MMSET has proprieties of a transcriptional co-factor, including localization to the nucleus, the ability to bind to sequence specific transcription factors including the zinc finger protein ZNF331 and transcriptional co-factors and histone deacetylases. In addition MMSET has histone methyl transferase activity which may be significantly different in terms of specificity when compared to other such proteins. These data lead to our overarching hypothesis that aberrant overexpression of MMSET leads to deregulated gene expression in B cells, contributing to the pathogenesis of myeloma.
Our specific aims are: 1) To determine the transcriptional functions of MMSET, 2) To determine the biological activity of MMSET on Myeloma Cell Growth using gain of function and loss of function strategies, 3) To characterize the MMSET transcriptional complex and partner proteins for gene regulation, 4) To identify genes regulated by MMSET relevant to Multiple Myeloma.

Public Health Relevance

MMSET protein is significantly overexpressed in myeloma cells harboring the t(4;14) translocation. These data lead to our overarching hypothesis that aberrant overexpression of MMSET leads to deregulated gene expression in B cells, contributing to the pathogenesis of myeloma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123204-05
Application #
8403653
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Howcroft, Thomas K
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$288,529
Indirect Cost
$99,330
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Saloura, Vassiliki; Cho, Hyun-Soo; Kiyotani, Kazuma et al. (2015) WHSC1 promotes oncogenesis through regulation of NIMA-related kinase-7 in squamous cell carcinoma of the head and neck. Mol Cancer Res 13:293-304
Oyer, J A; Huang, X; Zheng, Y et al. (2014) Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies. Leukemia 28:198-201
Licht, Jonathan D; Shortt, Jake; Johnstone, Ricky (2014) From anecdote to targeted therapy: the curious case of thalidomide in multiple myeloma. Cancer Cell 25:9-11
Min, D-J; Ezponda, T; Kim, M K et al. (2013) MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC. Leukemia 27:686-94
Ezponda, T; Popovic, R; Shah, M Y et al. (2013) The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer. Oncogene 32:2882-90
Popovic, Relja; Shah, Mrinal Y; Licht, Jonathan D (2013) Epigenetic therapy of hematological malignancies: where are we now? Ther Adv Hematol 4:81-91
Popovic, Relja; Licht, Jonathan D (2012) Emerging epigenetic targets and therapies in cancer medicine. Cancer Discov 2:405-13
Zheng, Yupeng; Sweet, Steve M M; Popovic, Relja et al. (2012) Total kinetic analysis reveals how combinatorial methylation patterns are established on lysines 27 and 36 of histone H3. Proc Natl Acad Sci U S A 109:13549-54
Martinez-Garcia, Eva; Popovic, Relja; Min, Dong-Joon et al. (2011) The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 117:211-20
Popovic, Relja; Licht, Jonathan D (2011) MEK and MAF in myeloma therapy. Blood 117:2300-2

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