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Principal Investigator: Nami McCarty
Organization: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
Fiscal Year: 2024
Award: $351,975
Funding agency: National Cancer Institute
Abstract:
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.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><APF-1><ATP-Dependent Proteolysis Factor 1><Address><Antibodies><Assay><Autologous Stem Cell Transplantation><Autophagocytosis><B blood cells><B cell><B cell malignancy><B cells><B lymphoid malignancy><B-Cells><B-Lymphocytes><B-cell><Binding><Bioassay><Biochemical><Biological Assay><Blood Plasma><Blood Vessels><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone Surface><Cancers><Catabolism><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Expansion><Cellular Growth><Clinical><Clinical Treatment><Complex><Cytolysis><DNA Alteration><DNA Sequence Alteration><DNA mutation><Dependence><Deubiquitination><Development><Drug resistance><Endothelium><Family><Family member><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Inactivation><Gene Silencing><Genetic mutation><Goals><HMG-20><Heterogeneity><Heterograft><Heterologous Transplantation><High Dose Chemotherapy><High Mobility Protein 20><Human><Intracellular Communication and Signaling><Link><Lysis><Macropain><Macroxyproteinase><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Metabolic Protein Degradation><Methods><Modern Man><Molecular><Molecular Interaction><Multicatalytic Proteinase><Multiple Myeloma><Neoplasms><Neoplastic Plasma Cell><Pathogenesis><Pathology><Pathway interactions><Patients><Plasma><Plasma Serum><Plasma-Cell Myeloma><Play><Predisposition><Process><Progenitor Cells><Proliferating><Prosome><Proteasome><Proteasome Endopeptidase Complex><Proteasome Inhibition><Proteasome Inhibitor><Protein Biosynthesis><Protein Family><Protein Turnover><Proteins><Proteosome><RBCC/TRIM Motif><Receptor Protein><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Refractory><Regulatory Protein Degradation><Relapse><Reporting><Resistance><Resistance development><Resistant development><Reticuloendothelial System, Serum, Plasma><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Role><Sampling><Sequence Alteration><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Susceptibility><System><TRIM Motif><Testing><Tracer><Transcript Expression Analyses><Transcript Expression Analysis><Tripartite Motif><Ubiquitin><Xenograft><Xenograft procedure><Xenotransplantation><aberrant folded protein><aberrant folded proteins><abnormal folded protein><abnormal folded proteins><analyze gene expression><autophagy><biological signal transduction><bone><cell growth><cell sorting><chemotherapy><clinical relevance><clinically relevant><de-ubiquitinase><de-ubiquitinating enzyme><developing resistance><developmental><drug resistant><gene expression analysis><gene expression assay><genomic alteration><improved><improved outcome><in vivo><inhibitor><insoluble aggregate><malignancy><member><misfolded protein><misfolded proteins><mouse model><multicatalytic endopeptidase complex><murine model><myeloma><myelomatosis><neoplasia><neoplasm recurrence><neoplasm/cancer><neoplastic growth><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathway><pre-clinical><preclinical><prevent><preventing><progenitor cell survival><progenitor survival><progenitor-like cell><protein aggregate><protein aggregation><protein complex><protein degradation><protein function><protein homeostasis><protein protein interaction><protein synthesis><proteostasis><proteotoxic><proteotoxic protein><proteotoxicity><proteotoxin><receptor><resistance to Drug><resistance to therapy><resistant><resistant to Drug><resistant to therapy><response to therapy><response to treatment><screening><screenings><social role><stem><stem cell survival><stem cells><stem-like cell><survival outcome><therapeutic resistance><therapeutic response><therapy resistant><therapy response><transcriptional profiling><transcriptional silencing><treatment resistance><treatment response><treatment responsiveness><trial regimen><trial treatment><ubiquitin isopeptidase><ubiquitin-specific isopeptidase><vascular><xeno-transplant><xeno-transplantation>