Abstract
Multiple myeloma (MM), the second most common hematopoietic malignancy, remains an incurable plasma cell (PC) neoplasm. While the proteasome inhibitor, bortezomib (Bz) has increased patient survival, resistance represents a major treatment obstacle as most patients ultimately relapse becoming refractory to additional Bz therapy. Current tests fail to detect emerging resistance; by the time patients acquire resistance, their prognosis is often poor. To establish immunophenotypic signatures that predict Bz sensitivity, we utilized Bz-sensitive and -resistant cell lines derived from tumors of the Bcl-XL/Myc mouse model of PC malignancy. We identified significantly reduced expression of two markers (CD93, CD69) in “acquired” (Bz-selected) resistant cells. Using this phenotypic signature, we isolated a subpopulation of cells from a drug-naïve, Bz-sensitive culture that displayed “innate” resistance to Bz. Although these genes were identified as biomarkers, they may indicate a mechanism for Bz-resistance through the loss of PC maturation which may be induced and/or selected by Bz. Significantly, induction of PC maturation in both “acquired” and “innate” resistant cells restored Bz sensitivity suggesting a novel therapeutic approach for reversing Bz resistance in refractory MM.
Highlights
Multiple myeloma (MM) is a fatal plasma cell (PC) malignancy representing the second most common hematopoietic cancer
The 589 and 595 cell line pairs were characterized by flow cytometry for a panel of 10 cell-surface proteins – CD93, CD69, CXCR4, CD20, CD19, CD22, CD38, CD138, B220, CD27– that were selected based on differential mRNA expression from the previous gene expression profiling study [10] and/or differential expression during normal B cell to PC maturation
The expression of most cell-surface markers remained unchanged between BzS and BzR cells, the differences between these cell types were most well-defined by cell surface CD93 and CD69 protein expression (Figure 1A); we chose to focus on these two markers and their significance as biomarkers of Bz sensitivity
Summary
Multiple myeloma (MM) is a fatal plasma cell (PC) malignancy representing the second most common hematopoietic cancer. Unlike normal PCs, which are fully differentiated, antibodyproducing B cells with a limited lifespan, malignant PCs retain their self-renewing capabilities and accumulate in the bone marrow resulting in malignancy [1,2]. Remarkable advances have been made in the treatment of MM that have improved patient survival, including bone marrow transplant and the discovery of novel chemotherapeutic agents including proteasome inhibitors. Proteasome inhibitors block the ability of the proteasomal complex to degrade overabundant, misfolded or damaged polyubiquitinated proteins [3,4]. The largescale production of antibodies by PCs requires the systematic degradation of excess proteins to maintain cellular homeostasis making the proteasome complex a successful chemotherapeutic target for MM [5]. Bz reversibly inhibits the PSMB5 subunit of the proteasome, primarily targeting its chymotrypsin-like activity [6] and has been widely used to treat MM in combination with agents such as melphalan, dexamethasone, thalidomide and other newer IMiDderivatives such as lenalidomide and pomalidomide [5]
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