Abstract B16: The pro-apoptotic effect of dexamethasone mediated by GILZ and Bim up-regulation is related to genetic heterogeneity of multiple myeloma.

Multiple myeloma (MM) is heterogeneous with respect to its causative molecular abnormalities and the treatment response of patients. Briefly, MM that are hyperdiploid or have a t(11;14) translocation have a better prognosis than those with t(4;14) or t(14;16) translocations. Dexamethasone (Dex) is widely used in all phases of MM treatment as induction, consolidation or maintenance. However, the mechanism of Dex sensitivity still remains elusive. In the present study, we analyzed the ability of Dex to induce cell death by Apo-2.7 staining in 33 human myeloma cell lines (HMCLs) representative of the molecular subsets carrying t(11;14), t(4;14) or t(14;16) translocations, which deregulate CCND1, MMSET and c-MAF, respectively. The mechanisms controlling Dex-induced apoptosis were evaluated by analyzing glucocorticoid receptor (GR), glucocorticoid-induced leucin zipper (GILZ) and Bcl-2 protein family expression in the different MM molecular subtypes. Transient knock-down of glucocorticoid-responsive proteins were performed to define their role in the pro-apoptotic effect of Dex. We first demonstrated that direct pro-apoptotic effect of Dex was related to the genetic heterogeneity of MM, since sensitive cell lines were restricted to t(14;16) and t(4;14) subgroups. We next demonstrated by transcriptomic Affymetrix analysis that GR expression was heterogeneous among the different molecular subtypes of HMCLs. MAF subgroup significantly expressed higher levels of GR than all other subgroups (p=0.02). This result was also confirmed on 300 newly diagnosed MM patients (p In conclusion, Dex exerted a direct anti-tumor effect on HMCLs of t(14;16) and t(4;14) molecular subgroups while t(11;14) subgroup was insensitive to it. This result suggested that conventional therapeutic approaches should be re-evaluated within molecular subgroups of MM patients to favor potential molecular subtype therapy based on rational preclinical data. Finally, while Dex interferes with multiple pathways, we begin to unravel its complex mechanism of action demonstrating that transactivation, inducing GILZ up-regulation, plays a pivotal role in Dex induced cell death through the regulation of the Bcl-2 protein network. Citation Format: Charlotte Kervoelen, Emmanuelle Menoret, Patricia Gomez-Bougie, Regis Bataille, Philippe Moreau, Catherine Pellat-Deceunynck, Martine Amiot. The pro-apoptotic effect of dexamethasone mediated by GILZ and Bim up-regulation is related to genetic heterogeneity of multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B16.