Expression of the NF‐κB targets BCL2 and BIRC5/Survivin characterizes small B‐cell and aggressive B‐cell lymphomas, respectively

Abstract

Nuclear factor kappa B (NF-kappaB) activation has been proposed as a cardinal feature of tumourigenesis, although the precise mechanism, frequency, relevance, and extent of NF-kappaB activation in lymphomas remain to be fully elucidated. In this study, expression profiling and tissue microarray studies of 209 and 323 non-Hodgkin's lymphomas (NHLs) respectively, including the most frequent sub-types of NHL, were employed to generate a hypothesis concerning the most common NF-kappaB targets in NHL. These analyses showed that NF-kappaB activation is a common phenomenon in NHL, resulting in the expression of distinct sets of NF-kappaB target genes, depending on the cell context. BCL2 and BIRC5/Survivin were identified as key NF-kappaB targets and their expression distinguished small and aggressive B-cell lymphomas, respectively. Interestingly, in the vast majority of B-cell lymphomas, the expression of these markers was mutually exclusive. A set of genes was identified whose expression correlates either with BIRC5/Survivin or with BCL2. BIRC5/Survivin expression, in contrast to BCL2, was associated with a signature of cell proliferation (overexpression of cell cycle control, DNA repair, and polymerase genes), which may contribute to the aggressive phenotype and poor prognosis of these lymphomas. Strikingly, mantle cell lymphoma and chronic lymphocytic leukaemia expressed highly elevated levels of BCL2 protein and mRNA, higher than that observed in reactive mantle zone cells or even in follicular lymphomas, where BCL2 expression is deregulated through the t(14;18) translocation. In parallel with this observation, BIRC5/Survivin expression was higher in Burkitt's lymphoma and diffuse large B-cell lymphoma than in non-tumoural germinal centre cells. In vitro studies confirmed that NF-kappaB activation contributes to the expression of both markers. In cell lines representing aggressive lymphomas, NF-kappaB inhibition resulted in a decrease in BIRC5/Survivin expression. Meanwhile, in chronic lymphocytic leukaemia (CLL)-derived lymphocytes, NF-kappaB inhibition resulted in a marked decrease in BCL2 expression.

Pathway-specific apoptotic gene expression profiling in chronic lymphocytic leukemia and follicular lymphoma

“…Our findings are in keeping with those of another study using CNIO OncoChip (cDNA microarray containing 6386 genes), which also found significant homogeneity among lymphomas of small lymphoid cells, including chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, and splenic marginal zone lymphoma. 23 Our conclusion is also consistent with that of the only other study directly comparing apoptotic gene Po0.006 (Fisher's exact test).…”

“…36 While BIRC5/ Survivin has been reported to be strongly expressed in chronic lymphocytic leukemia bone marrow by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry, 16 Sugahara et al 37 employed real-time reverse transcriptase polymerase chain reaction and found that BIRC5/ Survivin was downregulated in most cases of chronic lymphocytic leukemia, supporting the results of a recent microarray study. 23 In addition, Granziero et al 16 reported that survivin was detected only in the pseudofollicules of chronic lymphocytic leukemia lymph nodes through immunohistochemistry. This inconsistency in BIRC5/Survivin levels may be explained by the different techniques and specimens used.…”

“…Indeed, this practice is not uncommon in studies using group analysis. 23,31 We recognize that gene expression microarrays provide in vitro data primarily for generation of hypothesis. Thus, we have validated the upregulation of survivin in postchemotherapy chronic lymphocytic leukemia tumor samples with an in vivo method, immunohistochemistry.…”

Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy

“…As Bcl-2 is a target of nuclear factor-kappaB (NF-kB), which is involved in cancer metastasis and angiogenesis, 49,50 the activated Bcl-2 induces vascular endothelial growth factor (VEGF) expression in endothelial cells, resulting in the promotion of tumor angiogenesis. 51 The downregulation of Bcl-2 by AS Bcl-2 inhibits the activity of NF-kB and decreases the expression of VEGF, thereby inhibiting tumor angiogenesis.…”

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

“…The cooperating effects of MYC and BCL2 in lymphomagenesis have been shown in many studies. [4][5][6][7][8][9][10][11][12][13][14] Numerous case series of MYC/BCL2 double-hit lymphoma are reported in the literature. [15][16][17][18][19][20][21][22][23][24] MYC/ BCL2 DHLs represent B10% of all lymphomas that otherwise resemble diffuse large B-cell lymphoma (DLBCL).…”