Abstract
Abstract Multiple myeloma (MM), the second most common hematopoietic malignancy, is an incurable plasma cell neoplasm. The proteasome inhibitor, bortezomib (Bz), has been widely used to treat MM. However, patients eventually relapse due to drug resistance. Identifying signatures that distinguish Bz sensitive from resistant cells is critical for the development of novel approaches to reverse resistance. We have utilized isogenic pairs of Bz sensitive and resistant lines derived from the iMycCα/Bcl-xL mouse model of MM. This highly robust model resembles human MM based on gene expression, chromosomal abnormalities and progression of disease and response to therapy. In populations with an acquired resistance to Bz, we observed increased expression of Pax5 and AID and reduced expression of CD93 compared to parental Bz sensitive populations. Although most parental cells are CD93+, we have isolated a subpopulation of CD93- cells that expresses 20x more AID and display an innate resistance to Bz, while the CD93+ population remains sensitive. Time course analysis following low-dose Bz treatment indicates that Bz increases the expression and promotes the stabilization of Pax5 and AID demonstrating drug-induced changes in markers associated with B cell differentiation relating to the ultimate emergence of the resistance phenotype. Targeting B cell differentiation may represent a rational therapeutic approach to overcoming drug resistance.
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