thiostrepton and Lymphoma--Large-B-Cell--Diffuse

Comparative genome-wide expression profiling of malignant tumor counterparts across the human-mouse species barrier has a successful track record as a gene discovery tool in liver, breast, lung, prostate and other cancers, but has been largely neglected in studies on neoplasms of mature B-lymphocytes such as diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We used global gene expression profiles of DLBCL-like tumors that arose spontaneously in Myc-transgenic C57BL/6 mice as a phylogenetically conserved filter for analyzing the human DLBCL transcriptome. The human and mouse lymphomas were found to have 60 concordantly deregulated genes in common, including 8 genes that Cox hazard regression analysis associated with overall survival in a published landmark dataset of DLBCL. Genetic network analysis of the 60 genes followed by biological validation studies indicate FOXM1 as a candidate DLBCL and BL gene, supporting a number of studies contending that FOXM1 is a therapeutic target in mature B cell tumors. Our findings demonstrate the value of the "mouse filter" for genomic studies of human B-lineage neoplasms for which a vast knowledge base already exists.

Topics: Animals; Burkitt Lymphoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Forkhead Box Protein M1; Forkhead Transcription Factors; Gene Expression Profiling; Gene Regulatory Networks; Genes, Neoplasm; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Species Specificity; Thiostrepton

FoxM1 has been shown to play a critical role in the pathogenesis of various epithelial malignancies. However, its role in lymphoid malignancies has not been fully clarified. We, therefore, investigated the role of FoxM1 expression in a large cohort of diffuse large B-cell lymphoma samples and panel of cell lines.. FoxM1 expression was investigated in a large series of diffuse large B-cell lymphoma tissues in a tissue microarray format by immunohistochemistry. Apoptosis was measured by flow cytometry and protein expression was detected by immunoblotting using diffuse large B-cell lymphoma cell lines following treatment with either pharmacological inhibitor of FoxM1 or small interference RNA knockdown strategy. Invasion/migration and soft agar colony assays were also performed following treatment with FoxM1 inhibitor.. FoxM1 expression was detected in 84.6% of diffuse large B-cell lymphoma tumors and found to be significantly associated with proliferative tumor marker Ki67 (P<0.0001), matrix metalloproteinases-2 (P=0.0008), matrix metalloproteinases-9 (P=0.0002), S-phase kinase associated protein-2 (P<0.0001) and inversely associated with p27 expression (P=0.0215). Expression of small interference RNA targeted against FoxM1 or treatment of diffuse large B-cell lymphoma cells with thiostrepton caused its downregulation accompanied by decreased expression of matrix metalloproteinases-2 and matrix metalloproteinases-9. Inhibition of FoxM1 in diffuse large B-cell lymphoma cells also decreased invasive and migratory capability, and induced caspase dependent apoptosis via activation of the mitochondrial apoptotic pathway. Finally, combined thiostrepton and bortezomib at sub-toxic doses led to efficient apoptosis in diffuse large B-cell lymphoma cells.. Altogether, these results suggest that FoxM1 is over-expressed in the majority of diffuse large B-cell lymphoma samples. These data also indicate that targeting FoxM1 signaling can serve as a potential therapeutic modality in the management of diffuse large B-cell lymphoma.

Topics: Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Movement; Forkhead Box Protein M1; Forkhead Transcription Factors; Gene Expression; Humans; Immunohistochemistry; Ki-67 Antigen; Lymphoma, Large B-Cell, Diffuse; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Molecular Targeted Therapy; Primary Cell Culture; Proliferating Cell Nuclear Antigen; Pyrazines; RNA, Small Interfering; S-Phase Kinase-Associated Proteins; Signal Transduction; Thiostrepton; Tumor Stem Cell Assay