Progenitor Cells in Multiple Myeloma: In vivo Characterization and Clinical Significance.

Abstract

Multiple myeloma (MM), a bone marrow (BM) neoplasm of B-lymphocytes arrested in their maturation at the pre-plasma cell stage of differentiation, is the second most common hematologic malignancy in the U.S. Despite prolonged median survival with anti-myeloma strategies aimed at the tumor and its BM microenvironment, MM remains invariably fatal. Endothelial progenitor cells (EPCs) are CD133+/KDR+ cells that originate in the BM and play a key role in providing tumor neoangiogenesis, growth and MM progression. Using X-chromosome inactivation and RT-PCR analyses, our lab previously found EPCs from MM patients to be clonally restricted and genetically similar to tumor cells in approximately 60% of patients. Based on genetic similarity between EPCs and tumor cells in MM that we and other laboratories have demonstrated, my thesis explored the hypothesis that the clonal EPC population contains CD133+ MM precursor cells capable of self-renewal, and differentiation into a tumorigenic population. Results of my experiments strongly suggest that at least a subset of CD133+ cells qualify as MM progenitor cells evidenced by: (1) engraftment and differentiation of BM derived EPCs from MM patients in vivo in NOD/SCID mice; (2) in vitro and in vivo studies showing the differentiation of CD133+ cells from patients with MM into cells with a multiple myeloma cell phenotype (CD138/38+cells); (3) analysis of gene expression microarray studies showing upregulation of genes involved in stem cell function. Furthermore, I show the in vivo anti-myeloma effects of targeting Hsp70 whose gene expression is upregulated in MM. Taken together, my studies investigated MM pathogenesis through the in vivo characterization of progenitor cells as well as through genomic analyses, and targeting of a dysregulated pathway within EPCs and tumor cells which may be clinically effective.