Abstract
The genetic events that lead to aggressive transformation of cases of splenic marginal zone lymphoma (SMZL) after the chronic clinical stage have not been well understood. We aimed to find candidate genes associated with aggressive features of SMZL. We have successfully established two SMZL cell lines, designated SL-15 and SL-22, derived from the same patient’s tumor clone in chronic and aggressive phases, respectively. Microarray analysis identified cell cycle-associated genes—specifically PLK1—as the most significantly upregulated in primary aggressive SMZL cells compared with cells from chronic phase. EPHA4 and MS4A1 (CD20) were found to be downregulated dramatically. These gene expression patterns were reproduced in both cell lines. Genetic knockdown of PLK1 resulted in inhibition of cell proliferation and induction of apoptosis in SL-22 cells, which expressed higher levels of PLK1 than SL-15 cells. SL-22 cells needed higher concentrations of chemical PLK1 inhibitors to achieve greater effects. In addition, we found homozygous deletion of the MS4A1 gene as a newly identified molecular mechanism of CD20-negative conversion. Our findings are expected to stimulate further studies on whether PLK1 could be a potential therapeutic target for this tumor. Furthermore, cases with CD20-negatively converted lymphomas should be screened for the genomic loss of MS4A1.
Highlights
Splenic marginal zone lymphoma (SMZL), called splenic lymphoma with villous lymphocytes, is a rare B-cell neoplasm involving the spleen, bone marrow, and usually peripheral blood[1]
The Epstein–Barr virus (EBV)-immortalized SL-15 and SL-22 cell lines were established from a single patient with splenic marginal zone lymphoma (SMZL)
A few SMZL cell lines have been reported—one (VL51) from clinically stable SMZL21 and two (Karpas 1718 and UCH1) from the refractory form of the disease22, 23—the paired availability of our cell lines from a case of SMZL that manifested a long chronic phase before progression to an aggressive clinical course is invaluable in investigating the transformation mechanism of SMZL
Summary
Splenic marginal zone lymphoma (SMZL), called splenic lymphoma with villous lymphocytes, is a rare B-cell neoplasm involving the spleen, bone marrow, and usually peripheral blood[1]. Comparison of the primary lymphoma cells as well as their evolved cell lines derived from a single patient with SMZL in two different phases of the disease has provided an opportunity to study sequential gene expression profiles during such transformation. Microarray analysis showed a differential gene expression profile between SMZL cells derived from the chronic and aggressive clinical phases. Paired CD20-positive and -negative cell lines derived from the same clones before and after rituximab use, respectively, have been lacking In this context, our two lymphoma cell lines, SL-15 and SL-22, are valuable for studying the negative conversion of CD20. Our two lymphoma cell lines, SL-15 and SL-22, are valuable for studying the negative conversion of CD20 By utilizing these cell lines, we show here that genomic deletion of the MS4A1 (CD20) gene is another molecular mechanism in the loss of CD20 expression
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