Description
Telomeres, the specialized nucleoprotein structures at the ends of chromosomes, protect genomic DNA from exonucleolytic degradation and end-to-end fusion. Telomere shortening occurs at each DNA replication, which if unopposed, leads to its dysfunction and genomic instability associated with transformation. Telomerase, by extending telomeric DNA, provides additional replicative capacity. Telomerase re-activation is therefore observed in most cancers and immortalized cells. In multiple myeloma (MM) cells, we have preliminary data confirming high levels of telomerase, an inverse relationship between telomeres and telomerase activity, and induction of apoptosis by inhibiting telomerase. Additionally we have demonstrated that IL-6 and IGF-1 maintain telomerase activity in MM cells via NFkB and AKT pathways. Based on the hypothesis that maintenance of telomere function is critical to MM cell survival, we propose to investigate mechanisms maintaining telomere function in MM, thereby providing the framework for targeting telomerase in novel therapeutics. To achieve this goal, we will pursue the following specific aims: Specific Aim 1: To evaluate telomere function in MGUS, MM, and plasma cell leukemia. Our hypothesis is that the plasma cells in MGUS have lower telomerase and that critical shortening of telomeres occurring with time leads to a crisis with chromosomal instability; and that an increase in telomerase activity is associated with progression to MM. Specific Aim 2: To evaluate molecular mechanisms regulating increased telomerase activity and telomere maintenance in MM; Specific Aim 3: To evaluate telomerase/telomere-directed therapy in vitro and in vivo in animal models of human MM and in derived clinical studies.

1. To evaluate telomere function in MGUS, MM, and plasma cell leukemia.
2. To evaluate molecular mechanisms regulating increased telomerase activity and telomere maintenance in MM.
3. To evaluate telomerase/telomere-directed therapy in vitro and in vivo in animal models of human MM and in derived clinical studies.
   
   
   

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