B608 Syndecan-1 Mediates HGF/c-Met Endocytosis and Signaling in Myeloma Cells

Abstract

We have generated the first immuno-competent transgenic mouse model of multiple myeloma (MM), Vk*MYC, in which sporadic MYC activation in the germinal center is mediated by the same physiological process involved in the generation of immunoglobulin chromosome translocations. All of Vk*MYC mice develop monoclonal plasma cell (PC) expansion by 50 weeks of age, manifested by major M-spikes by SPEP. The PCs in Vk*MYC mice are fully differentiated, somatically mutated, have a low proliferation index and are found exclusively in the BM. Associated with a long lifespan, Vk*MYC mice develop anemia and diffuse bone disease, with sporadic occurrence of lytic bone lesions and hind limb paralysis. Furthermore, Vk*MYC mice MM displays therapeutic fidelity, as they show response to known clinically active anti-myeloma drugs, but not to drugs with no clinical activity as single agents. We have performed aCGH (Agilent 244K), using DNA from eight Vk*MYC CD138 selected MM cells. We found that the genomic complexity of Vk*MYC tumors is low, with only few all chromosome gains or losses, the only recurrent one being loss of chromosome Y in 3 out of 4 males. The most common abnormalities found are focal monoallelic deletions or amplification, targeting genes previously identified in MM. Among those, we found mono and bi-allelic deletion of Rb, amplification of BAFF-R and biallelic deletion of FHIT. We also detected a small region of amplification of mouse chromosome 3, syntenic to the larger region on human chromosome 1 frequently amplified in human MM and containing the Mcl1 gene, previously shown to be a crucial survival factor for MM cells. A focal homozygous deletion of several exons of a gene was identified in two tumors samples. Remarkably, a comparative analysis of the syntenic chromosomal region in human MM identified similar recurrent homozygous deletions in this putative novel tumor suppressor gene. Overall, these data indicate that the genomic complexity in this inbred strain of transgenic mice is significantly less then in patients with MM, simplifying the search for critical loci involved in MM tumorigenesis and further validate the Vk*MYC mice as a particularly faithful model of human MM.”