Abstract
Diffuse large B-cell lymphoma (DLBCL) may present initially in bone marrow, liver and spleen without any lymphadenopathy (referred to as BLS-type DLBCL), which is aggressive and frequently associated with hemophagocytic syndrome. Its tumorigenesis and molecular mechanisms warrant clarification. By gene microarray profiling with bioinformatics analysis, we found higher expression of the stem cell markers HOXA9 and NANOG, as well as BMP8B, CCR6 and S100A8 in BLS-type than conventional DLBCL. We further validated expression of these markers in a large cohort of DLBCL including BLS-type cases and found that expression of HOXA9 and NANOG correlated with inferior outcome and poor prognostic parameters. Functional studies with gene-overexpressed and gene-silenced DLBCL cell lines showed that expression of NANOG and HOXA9 promoted cell viability and inhibited apoptosis through suppression of G2 arrest in vitro and enhanced tumor formation and hepatosplenic infiltration in a tail-vein-injected mouse model. Additionally, HOXA9-transfected tumor cells showed significantly increased soft-agar clonogenic ability and tumor sphere formation. Interestingly, B cells with higher CCR6 expression revealed a higher chemotactic migration for CCL20. Taken together, our findings support the concept that tumor or precursor cells of BLS-type DLBCL are attracted by chemotaxis and home to the bone marrow, where the microenvironment promotes the expression of stem cell characteristics and aggressiveness of tumor cells.
Highlights
Abbreviations activated B-cell (ABC) Activated B-cell BLC B-lymphocyte chemoattractant BLS bOne marrow, liver and spleen BMP Bone morphogenetic protein DAB Diaminobenzidine DAVID Database for Annotation, Visualization and Integrated Discovery DLBCL Diffuse large B-cell lymphoma EBV Epstein-Barr virus glyceraldehyde 3-phosphate dehydrogenase (GAPDH) Glyceraldehyde 3-phosphate dehydrogenase germinal center B-cell (GCB) Germinal center B-cell IPA Ingenuity Pathway Analysis software IPI International Prognostic Index lymphoblastoid cell lines (LCLs) Lymphoblastoid cell lines lactate dehydrogenase (LDH) Lactate dehydrogenase
Since most cases of BLS-type DLBCL are linked to an activated B-cell immunophenotype with expression of BCL-6 and MUM-1/IRF-4, we hypothesized that tumor progenitor cells are activated B cells that colonize the bone marrow before neoplastic transformation
We focused on 5 relevant genes involved in stem cell signature (HOXA9, NANOG), chemotaxis (CCR6) and the microenvironment (BMP8B and S100A8/MRP8)
Summary
Abbreviations ABC Activated B-cell BLC B-lymphocyte chemoattractant BLS bOne marrow, liver and spleen BMP Bone morphogenetic protein DAB Diaminobenzidine DAVID Database for Annotation, Visualization and Integrated Discovery DLBCL Diffuse large B-cell lymphoma EBV Epstein-Barr virus GAPDH Glyceraldehyde 3-phosphate dehydrogenase GCB Germinal center B-cell IPA Ingenuity Pathway Analysis software IPI International Prognostic Index LCL Lymphoblastoid cell lines LDH Lactate dehydrogenase. The activated B-cell (ABC) subtype is an aggressive form of DLBCL associated with activation of the nuclear factor kB (NF-kB) and B-cell receptor signaling pathways. We have previously identified a distinct type of DLBCL, which initially involves bone marrow, liver and spleen without lymphadenopathy, referred to as BLS-type D LBCL11. Since most cases of BLS-type DLBCL are linked to an activated B-cell immunophenotype with expression of BCL-6 and MUM-1/IRF-4, we hypothesized that tumor progenitor cells are activated B cells that colonize the bone marrow before neoplastic transformation. The lymphoma cells may express genes relevant to the bone marrow microenvironment, such as stem cell features
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