Abstract
Multiple myeloma (MM) patients considered to be at high cytogenetic risk commonly fail to respond to standard treatment. A thorough understanding of the molecular mechanism of MM development is, therefore, needed. We endeavored to explore the transcriptional signature among different subgroups of newly diagnosed MM using gene chip-based expression microarray. Bone marrow samples of 15 newly diagnosed Thai MM patients were included. The chromosomal translocation t(4;14) was the most frequently identified genetic alteration in the high-risk subgroup. Cluster analysis from expression profiling demonstrated that high-risk MM have a distinctly different expression pattern compared to standard-risk patients. The most significant differentially expressed gene was UCHL1. Functional enrichment analysis by Gene Set Enrichment Analysis, FUNRICH, and Gene Ontology Panther pathway revealed the gene sets involved in cell cycle control to be enriched in the t(4;14) high-risk group. Interestingly, among the well-established downstream targets of UCHL1, only CCND2 was significantly expressed in the t(4;14) high-risk group. Suppression of UCHL1 protein level by LDN-5744 inhibitor could arrest the cell cycle in G1 phase in cell lines. These findings shed light on the molecular mechanism of UCHL1 in t(4;14) high-risk MM and support the evidence that alteration of the UCHL1 pathway may play a role in the pathogenesis of high-risk MM.
Highlights
Multiple myeloma (MM) or plasma cell myeloma (PCM) is a terminally differentiated B-cell neoplastic disorder that is characterized by the presence of clonal proliferation of malignant plasma cells (PCs) in bone marrow, and excessive monoclonal immunoglobulin, which is associated with multiple organ dysfunction [1]
UCHL1 was found to be predominantly overexpressed in the t(4;14) high cytogenetic risk group, which had an 80% prevalence of t(4;14) positivity
Gene set enrichment and pathway analysis revealed that UCHL1 regulates cell cycle control in t(4;14) high-risk MM
Summary
Multiple myeloma (MM) or plasma cell myeloma (PCM) is a terminally differentiated B-cell neoplastic disorder that is characterized by the presence of clonal proliferation of malignant plasma cells (PCs) in bone marrow, and excessive monoclonal immunoglobulin, which is associated with multiple organ dysfunction [1]. Improved understanding of the underlying molecular mechanism of MM pathogenesis is, needed so that more effective treatments can be developed. Several previous studies have attempted to investigate the molecular mechanisms underlying the pathogenesis of MM, including disease progression, tumor expansion, metastasis, treatment response, and MM drug resistance [4,5,6,7]. Microarray, which is one of many advanced technologies in cellular and molecular genetics, has yielded information and understanding about the clonal evolution, pathogenesis, and progression of MM, and this has led to the identification of biomarkers that can be used to develop potential targeted drug therapies [5, 8, 9]. The identification of prognostic factors is urgently needed in the high-risk subgroup of MM to improve treatment protocols and outcomes
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