Multiple myeloma (MM) is an incurable B cell malignancy that is characterized by the growth of neoplastic plasma cells within the bone marrow microenvironment. Despite progress in the clinical treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients develop resistance and become refractory to therapies. Drug resistance in MM is enabled by evolving genomic alterations as well as by contributions from stromal components in the bone marrow microenvironment. Specifically, the bone marrow provides a protective niche for slowly cycling/ quiescent stem-like MM cells that are not killed by chemotherapies. We have discovered sub-populations of MM stem-like cells that preferentially localize to osteoblastic niches of the bone marrow. Gene expression profiling revealed that a novel tripartite motif factor, TRIM44, is upregulated in MM stem-like cells isolated from the osteoblastic niche. TRIM family proteins function as autophagy-regulatory receptors and TRIM44 gene silencing decreases autophagy. In this project, we will investigate roles for TRIM44 and its links to protein homeostasis control during MM initiation, progression and resistance to therapy. Our working hypothesis is that TRIM44 plays integral roles in promoting quiescent MM stem cell survival within the bone marrow niche by regulating pathways involved in proteotoxic stress. Furthermore, we propose that targeting TRIM44 or its interacting proteins will result in diminished MM survival and improved outcome in response to therapy. To test this hypothesis, we will (i) analyze signaling pathways regulated by TRIM44 and determine how components of these pathways promote cell survival under proteotoxic stress; (ii) characterize novel substrates (from a recent mass spectrometry screen) that selectively bind to TRIM44 and determine the functional significance of these interactions in primary MM cells; and (iii) delineate the clinical relevance of these TRIM44-dependent pathways in MM pathogenesis and relapse using xenograft mouse models. Our long-term goal is to selectively inhibit TRIM44-dependent signaling pathways to benefit patients by reducing MM progression and/or blocking tumor recurrence after therapy.
Proposal Description: In this project, we will delineate functions for TRIM44 and its interacting molecules in MM stem-like cells using biochemical and molecular methods. The long-term goal is to establish TRIM44 as a new therapeutic target and ultimately develop inhibitors to eradicate MM stem-like cells in the bone marrow and improve patient survival.
