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Molecular Mechanisms Of Myeloma Cell Resistance To Apoptosis
By Rena Feinman, Arkansas Cancer Research Center
Cell homeostasis is controlled by a balance between proliferation, growth arrest and apoptosis. It is becoming increasingly evident that dysregulation of genes that control apoptosis contributes to the pathogenesis of disease such as cancer and autoimmune disease (1). In multiple myeloma, myeloma cells are terminally differentiated and fail to apoptose. Glucocorticoids such as dexamethasone (dex) are often used in the treatment of myeloma, either alone or in combination with cytotoxic agents. However, with prolonged treatment, patients develop resistance to these agents. It is well established that both glucocorticoids and chemotherapeutic drugs are potent inducers of cell death, by apoptosis (1). In fact, recent studies have demonstrated that dex-induced apoptosis in several human myeloma cell lines and interleukin-6 (IL-6), a B cell differentiation/ survival factor, protected them from dex-induced apoptosis (2,3). The molecular mechanisms that govern these processes are not fully understood. Restoration of the apoptopic response in myeloma cells is a central theme in the development of effective therapy for multiple myeloma.

In numerous lymphoid model systems, glucocorticoids have been shown to induce lymphoid cells to either undergo growth arrest or apoptosis. Yet, very little is known about its mode of action. Recent reports in the literature have proposed that steroids such as glucocorticoids and estrogen induce apoptosis by repressing transcription of 'survival' genes, (4,5). Dysregulation of both c-myc and transfected bcl-2 gene expression, two major 'survival' genes, have been implicated in the pathogenesis of myeloma. (6-8). Our preliminary studies have demonstrated that glucocorticoid susceptibility and bcl-2 expression are related inversely in several myeloma cell lines. Ectopic expression of bcl-2 protected a human IgA multiple myeloma derived cell line, ARP-1, from dex-mediated apoptosis. Mcy/max family of basic helix-loop helix-leucine zipper (bHLHzip) transcription factors appear to serve as intracellular targets for glucocorticoid's suppressive effects. The ability of the bHLHzip factors to form heterodimers and bind a specific DNA sequence, termed the E box, was impaired by dex. The difference in the sensitivity to glucocorticoid's cytotoxic effects between the parental and bcl-2 ARP-1 transfectants was due to the differential expression of the mcy/max family members. These studies lead to the hypothesis that crosstalk between myc/max family members and the bcl-2 family of survival factors is critical to myeloma apoptosis by dex and possibly other agents.

The overall aim of this project is to elucidate the molecular mechanisms involved in the functional coupling between mcy/max and bcl-2 family members that lead to the development of dex resistance in multiple myeloma. The identification of these signals will serve as a potential target for therapeutic intervention.
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