Prevention of MGUS Progression to MM by Modulating the Bone Marrow Microenvironment

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PROJECT SUMMARY The long-term objective of this work is to determine the functional role of the bone marrow microenvironment in regulating the plasma cell growth of monoclonal gammopathy of undetermined significance (MGUS), using multiple MGUS mouse models to define reliable biomarkers. Our findings should form the basis for designing novel treatment approaches to prevent MGUS progression to multiple myeloma (MM). MGUS is a precancerous, but clonal condition with aberrant DNA changes in plasma cells (PC). The prevalence of MGUS increases with age. It is 3.2% at 50 years but rises to 9% for those older than 85, suggesting that risk factors associated with aging play an important role in MGUS development. MGUS may progress to smoldering multiple myeloma (SMM) and/or to MM, requiring therapy. Therefore, it is particularly important to identify and subsequently target the risk factors associated with MGUS progression. By studying MGUS mouse models and primary human samples from MGUS patients, we have demonstrated that bone marrow cellular senescence related to aging, iron metabolism, and increased DKK1 in MGUS plasma cells are linked to MGUS progression. We hypothesize that changes in the bone marrow microenvironment (ME) alter gene expression of MGUS plasma cells and induce both bone destruction and immunosuppression resulting in MGUS plasma cell proliferation and disease escape from effective immune surveillance. We propose three specific aims to prove this hypothesis: (1) determine the role of cellular senescence of ME in MGUS progression; (2) determine the role of DKK1 in promoting MGUS progression in adoptive transgenic mice; and (3) determine cellular and molecular mechanisms of MGUS progression. Our goal is to discover novel therapeutic approaches to prevent human MGUS progression.