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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.

SUBMITTER: Chang KC

PROVIDER: S-EPMC7721882 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Chang Kung-Chao KC Chen Ruo-Yu RY Wang Yu-Chu YC Hung Liang-Yi LY Medeiros L Jeffrey LJ Chen Ya-Ping YP Chen Tsai-Yun TY Yang Jui-Chu JC Chiang Po-Min PM

Scientific reports 20201207 1

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 fu ...[more]

PMID: 33288848

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Project description:Microsatellite instability (MSI) has been investigated as a prognostic and predictive factor for chemotherapy in colorectal cancer and has recently been demonstrated to be predictive of the PD-1/PD-L1 checkpoint blockade response in various solid tumors. However, MSI status in diffuse large B-cell lymphomas (DLBCLs) has not been thoroughly explored. This study investigated MSI status in DLBCLs and analyzed the associations between MSI and clinicopathologic characteristics and clinical outcomes. Ninety-two cases of primary DLBCLs treated with R-CHOP/CHOP chemotherapy between 2009 and 2017 were collected. MSI detection was performed by the Promega MSI Analysis System. The protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry. The associations of MSI-H and MSI-L with progression-free survival (PFS) and overall survival (OS) were assessed by COX models and Kaplan-Meier curves. The correlations of complete response (CR) after R-CHOP/CHOP chemotherapy with MSI-H and MSI-L were examined by univariate and multivariate logistic regression analyses, respectively. 3 of 92 cases (3.2%) were high MSI (MSI-H), and 9 cases (9/92, 9.8%) exhibited low MSI (MSI-L). One case with MSI-H showed negative expression of MSH2 and MSH6. Univariate analysis indicated that MSI-L was correlated with poor response to R-CHOP/CHOP chemotherapy in DLBCLs (OR, 0.178; 95% CI, 0.041-0.776; P = .022). Multivariate analysis showed that MSI-L was an independent predictive factor for non-CR to R-CHOP/CHOP chemotherapy (OR, 0.144; 95% CI, 0.027-0.761; P = .023). Kaplan-Meier curves showed that there was a trend that MSI-H patients had favorable PFS (P = .36) and OS (P = .48), which did not have statistical significance and MSI-L was not significantly correlated with PFS (P = .24) and OS (P = .52).Our study indicated that there existed MSI-H and MSI-L in DLBCLs. MSI-L could be an independent predictive factor for the chemotherapy response in DLBCLs.

Dataset Information

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

Publications

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

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