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Extranodal dissemination was an important feature of aggressive B-cell lymphoma. Due to the lack of available animal model, the causes of extranodal dissemination of lymphoma were largely unknown. Here, we identified a novel cell line, named MA-K, which originated from the Eμ-Myc;Cdkn2a-/-cell line, named MA-LN in this study. Compared to MA-LN, MA-K tended to disseminate in the kidney rather than lymph nodes in lymphoma transplantation model, resembling human primary renal lymphoma. The transcriptome analysis revealed that MA-K had undergone the transcriptional evolution during the culture. Specialized transcriptional pattern analysis, we proposed in this study, identified that FOXO1-BTG1-MYD88 pattern was formed in MA-K. Further analysis found that translation pathway was the most enriched pathway in specially expressed genes (SEGs) in MA-K. Among the SEGs, 3 up-regulated genes, RPLP2, RPS16 and MRPS16, and 5 down-regulated genes, SSPN, CD52, ANKRD37, CCDC82 and VPREB3, in MA-K were identified as promising biomarkers to predict the clinical outcomes of human DLBCL. Moreover, the joint expression of the 5-gene signature could effectively predict clinical outcomes of human DLBCL in triple groups. These findings suggested that the MA-K cell line had strong clinical relevance with human aggressive B-cell lymphoma. Moreover, the MA-K primary renal lymphoma model, as a novel syngenetic mouse model, would be greatly useful for both the basic research on lymphoma dissemination and preclinical efficacy evaluation of chemotherapy and immunotherapy.

Targeted therapy was a promising therapy for aggressive B-cell lymphoma. However, drug resistance was still an unavoidable problem. Here, we explored the effect of EFNB1 on drug response. Analysis of IC50 data showed that high level of EFNB1 was associated with resistance to most targeted drugs targeting BCR in human DLBCL cell lines. Drug response assay showed that Efnb1 could enhance SRC phosphorylation and increased the sensitivity of cells to SRC inhibitors. Meanwhile, Efnb1 could sensitize cells to most cytotoxic drugs, especially DOX and VCR. Efnb1 could confer cells sensitivity to VCR by enhancing the phosphorylation of Stmn1 at serine 28. Survival analysis revealed that the expression level of genes phosphorylated in Efnb1 cells were associated with poor prognosis of human DLBC. Together, this study revealed that EFNB1 level, as a non-genetic mechanism, greatly affected drug response of targeted drugs and cytotoxic drugs through the phosphorylation network. Our findings would provide important insights into EFNB1-SRC activated B-cell lymphoma and efficacy evaluation.

Background: Receptor tyrosine kinases (RTKs) are key signal molecules for sustaining proliferative signaling and abnormal of RTKs appears in many cancers, including Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC).Methods: Cluster analysis based on RNA-seq and RPPA data were calculated to establish novel signature for molecular subtyping of DLBC. Principal component analysis (PCA) was used to evaluation relationship of selected genes.Results: EPHB4, EPHB6, EFNA3, EFNA4, EFNB1 are 5 specific genes in DLBC and their expression level are significantly relevant to poor prognosis. Integration analysis of DLBC Expr-Ab signature discovered five DLBC related Eph-Ephrin genes may be involved in epigenetic regulation in DLBC progress. Four novel clusters based on Expr-Ab are generated and we first link five Eph-Ephrin to well-defined oncogenes as following: EPHB4-BCL6; EFNA3/EFNA4-MYC; EPHB6-EZH2; EFNB1-Epigenetic modulators. Drug response data involving 13 traditional and targeting drugsConclusions: Expr-Ab signature we established in this study indicates the power of both RNA-seq and RPPA data in developing and evaluating precision regimens. We also highlight Eph-Ephrin, as surface proteins, are powerful potentially biomarkers. Our finding underlines Eph-Ephrin as biomarkers for predicting prognosis and precision regimen for patients with lymphoma.