Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis

Abstract

Splenic marginal zone lymphoma (SMZL)is a newly recognized lymphoma type whose precise molecular pathogenesis is still essentially unknown. This hampers differential diagnosis with other small Bcell malignancies. With the aim of characterizing this tumor more comprehensively, and of identifying new diagnostic and prognostic markers, we performed cDNA microarray expression profiling and tissue microarray (TMA) immunohistochemical studies in a relatively large series of 44 SMZLs. The results were related to immunoglobulin heavy chain variable region (IgV H ) mutational status and clinical outcome. SMZLs display a largely homogenous signature, implying the existence of a single molecular entity. Of the genes deregulated in SMZLs, special mention may be made of the genes involved in B-cell receptor (BCR) signaling, tumor necrosis factor (TNF) signaling and nuclear factor-B (NF-B) activation, such as SYK, BTK, BIRC3, TRAF3, and LTB. Other genes observed were SELL and LPXN, which were highly expressed in spleen, and lymphoma oncogenes, such as ARHH and TCL1. In contrast, the genes CAV1, CAV2, and GNG11 located in 7q31, a commonly deleted area, were downregulated in the entire series. A comparison with the genes comprising the signature of other small B-cell lymphomas identified 3 genes whose expression distinguishes SMZL, namely ILF1, SENATAXIN, and CD40. IntroductionSplenic marginal zone lymphoma (SMZL) is a newly described lymphoma type, whose precise diagnosis, patient stratification into risk groups, and appropriate treatment is still in need of further investigation. [1][2][3] The diagnosis of SMZL is often hindered by the lack of conclusive immunophenotypical or molecular data concerning differences from chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). The expression of CyclinD1 and B-cell lymphoma 6 (Bcl6) can contribute to the diagnosis of MCL or FL, but this is occasionally difficult to measure in samples of peripheral blood or bone marrow from CLL and MCL cases. Consequently, the diagnosis of SMZL is still characterized by strikingly low reproducibility. Even when a correct diagnosis has been established, the clinical course is appreciably variable, with a subset of cases showing frequent and early relapses, and shorter survival. Although patients with this aggressive SMZL form can be recognized by the absence of immunoglobulin heavy chain variable region (IgV H ) somatic mutation or the 7q31 deletion, 4 this is not accurate enough to allow stratification of patients into different risk groups receiving risk-adjusted specific treatments. Finally, the available treatments for SMZL essentially overlap those of other small B-cell non-Hodgkin lymphomas (NHLs), and the molecular data obtained so far for SMZL are insufficient to form the basis for the proposal of new therapeutic targets.Lymphoma diagnosis and knowledge has been facilitated in recent years by the development of high-throughput molecular tools, such as expression microarrays aimed at quantifying the expr...

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

“…34,36 Although the proteins that have a role in the pathogenesis of MALT lymphoma are still largely unknown (except for those involved in the NF-kB pathway), we compared the gastric MALT lymphoma expression patterns found in this study with the chromosomal locations of genes encoding proteins that are involved in the NF-kB pathway and/or proteins with previously reported altered expression in marginal zone lymphoma. [37][38][39][40][41][42][43][44][45][46] Of interest is that 18q21/MALT1 is overexpressed in all the three groups, consistent with reported MALT1 overexpression in MALT lymphomas regardless of the presence or absence of a t(11;18)(q21;q21). Overexpression of 11q21/ API2 did only occur in the two t(11;18)(q21;q21)-positive groups and not in the t(11;18)(q21;q21)-negative group and may be explained by API2-MALT-induced transcriptional activation of the API2 gene through NF-kB binding elements.…”

Nuclear bcl10 expression characterizes a group of ocular adnexa MALT lymphomas with shorter failure-free survival

“…Two selected 1-mm cores from different areas were included, along with two separate reactive tonsil tissues as a control to ensure the quality, reproducibility and homogeneous staining of slides. [17][18][19][20] …”

“…[17][18][19][20] The use of tissue microarrays could be particularly useful in this context, since tumoral specimens in ocular adnexa lymphomas are frequently small, fully embedded in paraffin, and require microdissection or tissue-core selection to guarantee that the analysis reports on the features of the tumoral cells.…”

“…In order to elucidate the biology of ocular adnexa MALT lymphomas we have analyzed a tissue microarray including a large series of 39 cases with a panel of antibodies and probes directed against molecules known to be involved in B-cell differentiation, cell cycle and apoptosis control, [17][18][19][20] and, for control purposes, compared them with some non-MALT lymphomas from the same anatomical region. Moreover, we have included in the analysis a tissue-microarray in situ hybridization study of the apoptotic index (TdT-mediated biotin-dUTP nickedend labeling (TUNEL)), and of t(11;18)(q21;q21) and t(14;18)(q32;q21), which are characteristic translocations of MALT lymphomas.…”

Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas

“…SYK encodes a cytoplasmic PTK, which is important in proliferation and prosurvival signaling [4][5][6][7] and is expressed in a variety of hematopoietic cells, including normal B lymphocytes 8 and most B-cell lymphomas. 5,[9][10][11][12] Normal peripheral T cells, however, generally lack Syk protein expression. 13 In the current work, we demonstrate that Syk is overexpressed in the majority of PTCLs, despite the absence of SYK/ITK translocations in most cases.…”