Stem cell characteristics promote aggressiveness of diffuse large B-cell lymphoma

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.

PARK2 Regulates eIF4B-Driven Lymphomagenesis

“…Next, we studied the transformative impact of PARK2 using the clonogenic assay (colony formation assay). It is a widely used experimental approach to assess the transformed characteristics of cells in vitro (11,(22)(23)(24). In agreement with our proliferative and oncogenic studies, decreased PARK2 expression enhanced colony formation in GM-B cells (Fig.…”

Baseline PET-CT evaluation of Bone Marrow-Liver-Spleen Type of Diffuse Large B-Cell Lymphoma: A Rare Aggressive Extranodal Lymphoma

“…Bone marrow biopsy usually reveals hemophagocytosis and an interstitial distribution of large lymphoma cells with a mature B-cell phenotype. In another study by gene microarray profiling with bioinformatics analysis, higher expression of the stem cell markers HOXA9 and NANOG, as well as BMP8B, CCR6 and S100A8 were found in BLS-type than conventional DLBCL (14).…”

Downregulation of hsa‐miR‐548d‐3p and overexpression of HOXA9 in diffuse large B‐cell lymphoma patients and the risk of R‐CHOP chemotherapy resistance and disease progression

“…The lifespan of these patients was significantly shorter than those without overexpression of HOXA9 mRNA. The study suggested that DLBCL patients with overexpression of HOXA9 mRNA are 2.540 times more likely to have shorter overall survival period [hazard ratio = 2.540, 95%CI (1.132 to 5.697)] 22 . In addition, patients with high level of HOXA9 2.387 times are more likely having shorter progression free survival period (hazard ratio = 2.387, 95%CI = [0.876, 6.545]) 23 …”