MYELOMA SURVIVAL · Identification of factors that promote the survival of multiple myeloma
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-10-01 → 2009-09-30
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- EIF
Lines connect the coordinator with its partners.
Results in brief
Final Activity Report Summary - MYELOMA SURVIVAL (Identification of Factors that Promote the Survival of Multiple Myeloma)
Multiple myeloma (MM) is an incurable devastating cancer responsible for approximately 1-2% of lethality from cancer. MM is a unique type of cancer because it arises from a special cell type called plasma cell. Normally plasma cells are responsible for generating antibodies. They reside in the bone marrow and their numbers are carefully regulated. However, in processes that we do not fully understand, a single plasma cell loose its regulation, starts to proliferate uncontrollably and yields after several years MM. Because of the uniqueness of this disease, we hypothesised that MM utilise special biochemical reactions that allow it to proliferate and maintain antibody secretion. The main objective of this study was to identify biochemical processes that promote the survival of MM and plasma cells with the hope that inhibition of these pathways may result in novel therapeutic modalities to MM. In brief, we discovered that synthesis of special lipid molecules in plasma cells, termed ceramides, plays an important element in plasma cells and not in other cell types. In plasma cells ceramide synthesis supports antibody production. In a paper published in the Journal of Immunology we described that treatment of plasma cells with an inhibitor for ceramide synthesis called fumonisin B1 results in inhibition of antibody production and aberrations in protein modifications. If true also to MM, we believe that this discovery may have an important meaning for MM treatment. A second discovery we made concerned the transcription factor XBP-1. This factor is necessary for generation of plasma cells and plays an important role in the survival of MM. We previously showed that XBP-1 is degraded by the proteasome in seconds. We hypothesised that the mechanism of XBP-1 degradation is unusual and should be looked at in more details. In a paper submitted to FEBS letters and is currently under revision, we show that XBP-1 directly binds the proteasome and this interaction is mediated by multiple contact sites. The direct interaction with the proteasome is sufficient to promote XBP-1 degradation in vitro. Other projects are on-going in the lab that looks at the control of protein synthesis in plasma cells and characterisation of apoptosis in MM.
Data: CORDIS, © European Union
Project objective
Plasma cells are responsible for secretion of immunoglobulins (Ig) into the bloodstream, which constitute the humoral immune response. XBP-1 is a transcription factor necessary for the terminal differentiation of B cells into plasma cells. XBP-1 is required for the synthesis and the maintenance of high levels of Ig, and plays a critical role in setting the conditions for their assembly and secretion. Multiple myeloma (MM) is the cancer of plasma cells, and in most cases this cancer retains the capacity to secrete high levels of Ig. MM is impervious to conventional chemotherapies, and constitutes 2% of total deaths from cancer. Recent evidence shows that XBP-1 promotes survival of MM cells. Since XBP-1 is destroyed with a half-life of minutes, we shall explore the mechanisms responsible for its degradation, as factors that may promote MM survival. We shall express recombinant XBP-1, and study its degradation by the proteasome in a cell free assay. In addition, we will use an RNA interference screening to identify genes required for the degradation of XBP-1. Bortezomib is a newly approved drug for MM, which blocks the proteasome.The reasons why MM shows remarkable sensitivity to bortezomib are unknown. Utilizing cells resistance to proteasome inhibition, we will strive to identify genes and biochemical pathways that confer resistance of MM to treatment with bortezomib. This study may identify novel targets and pathways for the therapy of MM, and provide better understanding of the regulation of XBP-1 levels.The overall aim is to combat cancer by broadening the knowledge base on molecular mechanisms underlying chemotherapy resistance. In accordance with the IRG objectives, my proposal will implement and transfer to Europe the technology developed at the Whitehead Institute in Cambridge, Mass. USA, where I spent the last 5 years (postdoctoral training), and will strengthen the existing collaboration with Whitehead researchers.
Original text from CORDIS.
Participants
- THE HEBREW UNIVERSITY OF JERUSALEM · JERUSALEMCoordinatorIsrael
Links
Data: CORDIS, © European Union