Final Report Summary - TOP (TOwards Personalized medicine: defining the role of the bone marrow microenvironment in multiple myeloma)
Multiple myeloma (MM) is the second most common B cell neoplasm characterized by a clonal expansion of malignant plasma cells in the BM. MM accounts for 1% of all cancer-related deaths, with an incidence adjusted for age of around 3 per 100000 habitants in Europe. Recent studies have shown that all MMs are preceded by a pre-malignant expansion of plasma cells called monoclonal gammopathy of undetermined significance (MGUS). MGUS has a prevalence of 3% and 5% in persons older than 50 and 70 years respectively, with a risk of progression to MM of 1% per year. So far no discriminative genetic or phenotypic markers that can distinguish MGUS from MM tumour cells have been identified, which makes it impossible to predict if and when an MGUS will progress to MM. Despite intense efforts and an enormous increase in our understanding of the pathogenesis of MM, the median survival after conventional treatments is 3-4 years, whereas high-dose treatment followed by autologous stem cell transplantation can extend the median survival to 5-7 years. The evolution of MM is nowadays viewed as a multistep model in which MGUS progresses through smoldering (asymptomatic) MM, symptomatic (intramedullary) MM, and extramedullary MM/ plasma cell leukaemia.
Although the plasma cells of MGUS and MM can harbour a wide variety of translocation and other genetic aberrations, the absence of real definitive genetic differences between MGUS and MM, and the inability of MM cells to grow outside the BM, underscores the essential role of the BM microenvironment in development, maintenance, and progression of MM. In this project, a recently developed humanized MM mouse model (Groen et al. Blood 2012), carrying a human bone environment, will be combined with a thorough analysis of the BM microenvironment in MM, in relation to disease progression from MGUS to MM. To this end, a comparison will be made between BMSCs from MGUS and MM patients with those from healthy volunteers, on genomic, molecular, and functional level. Using this approach, we have now performed gene expression profiling analyzing the transcriptome of BMSCs obtained from 8 healthy donors, 16 MGUS, 21 MM and 4 acute myeloid leukemia patients. These analyses have confirmed previously published data, as well as generated novel insights into the genes and their respective pathways contributing to the diseased BM environment in MM. Besides, the creation of a modified version of our humanized mouse model allowed us to implement and compare results from the patient samples in/with our humanized MM mouse model and capture the "priming" effect of MM cells on MSCs, and finally identify key players in the interactions of MM plasma cell with the BM microenvironment, MM drug resistance, and bone development, i.e. osteolytic lesions. Interestingly, we have identified FDA/EMEA-approved medication that can target some of these processes. Besides, these therapeutic options might not be limited to MM, but could also be of use in breast cancer induced osteolytic lesions and osteoporosis.
Although the plasma cells of MGUS and MM can harbour a wide variety of translocation and other genetic aberrations, the absence of real definitive genetic differences between MGUS and MM, and the inability of MM cells to grow outside the BM, underscores the essential role of the BM microenvironment in development, maintenance, and progression of MM. In this project, a recently developed humanized MM mouse model (Groen et al. Blood 2012), carrying a human bone environment, will be combined with a thorough analysis of the BM microenvironment in MM, in relation to disease progression from MGUS to MM. To this end, a comparison will be made between BMSCs from MGUS and MM patients with those from healthy volunteers, on genomic, molecular, and functional level. Using this approach, we have now performed gene expression profiling analyzing the transcriptome of BMSCs obtained from 8 healthy donors, 16 MGUS, 21 MM and 4 acute myeloid leukemia patients. These analyses have confirmed previously published data, as well as generated novel insights into the genes and their respective pathways contributing to the diseased BM environment in MM. Besides, the creation of a modified version of our humanized mouse model allowed us to implement and compare results from the patient samples in/with our humanized MM mouse model and capture the "priming" effect of MM cells on MSCs, and finally identify key players in the interactions of MM plasma cell with the BM microenvironment, MM drug resistance, and bone development, i.e. osteolytic lesions. Interestingly, we have identified FDA/EMEA-approved medication that can target some of these processes. Besides, these therapeutic options might not be limited to MM, but could also be of use in breast cancer induced osteolytic lesions and osteoporosis.