Multiple myeloma is a malignant tumor of plasma cell origin. Plasma cells, that differentiate from activated B cells, are normally non-dividing cells that produce large quantities of antibodies of various isotypes. Contrary to plasma cells, myeloma cells divide actively and, as the disease progresses, acquire the capacity to invade various body compartments. Similar to other tumors of lymphoid origin, the cause for multiple myelomas is linked to chromosomal translocations. In many instances, these translocations place the cell cycle and cell differentiation regulating genes under the control of the highly potent immunoglobulin heavy chain (IgH) gene enhancer/promoter. The overexpression of IgH enhancer/promoter driven genes such as cyclin D1, cyclin D3 or c-maf is likely to contribute to myeloma cell proliferation.
This research is based on recent findings that suggest an important role of the histone methyltransferase MMSET (Multiple Myeloma SET domain protein) in malignant progression of multiple myeloma. In about 15% of all myeloma cases the t(4:14) translocation brings mmset gene under the control of the µ enhancer followed by increased expression of the protein. It is not currently known how the increased expression of MMSET in plasma cells is translated into myeloma development and/or/progression. Provided that MMSET acts as a histone methyltransferase, we propose that the developmental program of normal and neoplastic plasma cells is regulated by this enzyme. Specifically, we hypothesize that deregulation of MMSET in plasma cells alters the epigenetic signature and contributes to the disease initiation and or progression.
The goal of the current research (in the 2nd year of funding) is to gain further insight into the biological consequences of the conditional overexpression or inactivation of MMSET in B- and plasma cells in mice. To achieve this goal, we propose the following specific aims:
- To define the role of MMSET in normal plasma- and myeloma cell development and explore how increased plasma cell proliferation is translated in disease initiation and/or progression.
- To identify the genetic network directly controlled by MMSET in B cells: the whole genome and the whole transcriptome approaches.
During the first year of funding, we have established all the molecular tools needed to address these questions. Specifically, we have created strains of mice overexpressing MMSET or an enzymatically inactivated protein (MMSET ΔSET) in B cells. Importanly, our preliminary data demonstrate that B cells overexpressing MMSET proliferate better than their wild type counterparts, resembling the situation with malignant cells in myelomas. The second year of funding will allow us to focus on animal models of tumorigenesis and refine our understanding of the role this methyltransferase is playing under normal and malignant conditions.