Gene Profiling Of Multiple Myeloma: Mapk Pathway Deregulation, Which Is Regulated By Pim-1 And Mos, Is Associated With Relapse Within 6 Months After Autosct In Mm Patients

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Dynamic interplay between bone marrow stromal cells (BMSCs) and MM cells regulated the relapsed MM after autologous bone marrow transplantation (ABMT). In this study, we performed gene expression profiling with microarray data to better dissect the molecular phenotypes and prognoses of relapsed multiple myeloma (MM). Using gene expression and clinical data, we applied gene expression signatures reflecting deregulation of oncogenic pathways to highlight molecular changes in bone marrow aspirate from 28 patients with relapsed MM. The patient subgroups were defined according to relapse-free interval, within 6 months versus more than 6 months. The microarray results revealed that dyregulation of MAPK pathway was associated with relapse within 6 months after ABMT. Among them, the expression of PIM-1 gene and MOS gene was higher in samples from patients with relapsed MM than MM cell lines (p=0.0037; p=0.0021). Also, IL-6, sIL-6R, and HGF expression in patients who relapsed within 6 months after ABMT was higher than the patients whose relapse-free interval were longer than 6 months. Treatment of shRNA PIM-1 gene and shRNA MOS gene in U266 and MOLP8 dramatically led to decreasing IL-6/sIL-6R mediated ERK phosphorylation and HGF-mediated MET phosphorylation. Similar results were noted for cluster genes for PIM-1/MOS. Especially, functional analysis of PIM-1 leads to inactivate the MAPK pathway through regulating p38 mediated signaling and Wnt/β-catenin pathway. Recent studies suggested that p38 activity in myeloma inhibits osteoblast differentiation and bone formation, but also enhances osteoclast maturation and bone resorption. p38 regulated the expression and secretion of the Wnt pathway antagonist DKK-1 and the monocyte chemoattractant MCP-1. Conclusionally, Our analysis suggested that MOS gene and PIM-1, which regulates MAPK pathway, is a noble prognostic marker for relapse of MM. The importance of the PIM-1-MOS-MAPK pathway as a prognostic marker in relapsed MM should be reassessed in the novel therapeutic agent era. Citation Format: Woo June Jung, Kwang-Sung Ahn, Chansu Lee, Youngil Koh, Hyun Jung Lee, Hyo Jung Kim, Hwi-Joong Yoon, Sung-Soo Yoon. Gene profiling of multiple myeloma: MAPK pathway deregulation, which is regulated by PIM-1 and MOS, is associated with relapse within 6 months after autoSCT in MM patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1152. doi:10.1158/1538-7445.AM2014-1152