Novel Mouse Models of Human Myeloma

The majority of studies to date of human multiple myeloma (MM) cells in vivo have utilized xenograft models. Specifically, human MM cells have been injected subcutaneously into SCID mice in order to evaluate the ability of agents to inhibit tumor cell growth and associated angiogenesis, as well as prolong host survival^1-3 . A model in which fluorochrome-labeled human MM cells are injected via the tail vein into SCID mice and then migrate and grow primarily in bone has allowed for gene microarray and proteomic studies in MM cells vs. BM as MM cells bind in the BM milieu, both before and after novel drug treatments⁴ . Direct injection of MM cells into fetal bone chips implanted subcutaneously into SCID mice (SCID hu model) allows for the study of human MM cells in the context of human extracellular matrix proteins and accessory cells in vivo⁵ . This model has been refined by injecting fluorochrome-labeled cytokine-dependent MM cells directly into human bone grafts within SCID mice, which allows for evaluation of cellular and gene changes triggered in tumor vs. BM by MM cell binding, both before and after treatment with novel agents^6,7 . These models have therefore delineated the genetic changes and sequelae induced when MM cells bind to the BM, and conversely validated the ability of novel agents to abrogate these genetic changes and induce tumor cell cytotoxicity even in the BM milieu.

XBP-1 is a transcription factor required for plasma cell differentiation, which is also highly expressed at a gene and protein level in MM cells vs. normal plasma cells^8-10 . Interleukin-6 (IL-6) upregulates both transcript and protein levels of XBP-1 in MM cells; conversely, knockdown of XBP-1 decreases viability and sensitizes MM cells to dexamethasone. The novel agent, 2-methoxyestradiol, downregulates XBP-1 transcripts and protein in MM cells⁹ , whereas the proteasome inhibitor Bortezomib works, at least in part, by targeting XBP-1 and the unfolded protein response⁸ .