Expression of HGAL in primary cutaneous large B-cell lymphomas: evidence for germinal center derivation of primary cutaneous follicular lymphoma

Reproducible expert-independent flow-cytometric criteria for the differential diagnoses between mature B-cell neoplasms are lacking. We developed an algorithm-driven classification for these lymphomas by flow cytometry and compared it to the WHO gold standard diagnosis. Overall, 662 samples from 662 patients representing nine disease categories were analyzed at 9 laboratories using the previously published EuroFlow 5-tube-8-color B-cell chronic lymphoproliferative disease antibody panel. Expression levels of all 26 markers from the panel were plotted by B-cell entity to construct a univariate, fully standardized diagnostic reference library. For multivariate data analysis we subsequently utilized Canonical Correlation Analysis of 176 training cases to project the multi-dimensional space of all 26 immunophenotypic parameters into 36 two-dimensional plots for each possible pair-wise differential diagnosis. Diagnostic boundaries were fitted according to the distribution of the immunophenotypes of a given differential diagnosis. A diagnostic algorithm based on these projections was developed and subsequently validated using 486 independent cases. Negative predictive values exceeding 92.1% were observed for all disease categories except for follicular lymphoma. Particularly high positive predictive values were returned in chronic lymphocytic leukemia (99.1%), hairy cell leukemia (97.2%), follicular lymphoma (97.2%) and mantle cell lymphoma (95.4%). Burkitt and CD10+ diffuse large B-cell lymphomas were difficult to distinguish by the algorithm. A similar ambiguity was observed between marginal zone, lymphoplasmacytic, and CD10- diffuse large B-cell lymphomas. The specificity of the approach exceeded 98% for all entities. The univariate immunophenotypic library and the multivariate expert-independent diagnostic algorithm might contribute to increased reproducibility of future diagnostics in mature B-cell neoplasms.

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CD44s and CD44v6 Are Predominantly Expressed in the Non-germinal Center B-Cell-like Type of Diffuse Large B-Cell Lymphomas

The Korean Journal of Pathology ◽

10.4132/koreanjpathol.2011.45.6.589 ◽

2011 ◽

Vol 45 (6) ◽

pp. 589

Author(s):

Kyueng-Whan Min ◽

Young-Ha Oh ◽

Chan-Kum Park ◽

So-Dug Lim ◽

Wan-Seop Kim

Keyword(s):

B Cell ◽

Germinal Center ◽

B Cell Lymphomas ◽

Germinal Center B Cell ◽

Large B Cell

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An additional segment at 1p36 derived from der(18)t(14;18) in patients with diffuse large B-cell lymphomas transformed from follicular lymphoma

Annals of Hematology ◽

10.1007/s00277-004-0995-z ◽

2005 ◽

Vol 84 (7) ◽

pp. 474-476 ◽

Cited By ~ 5

Author(s):

Kenichi Nomura ◽

Yumiko Kanda-Akano ◽

Daisuke Shimizu ◽

Takashi Okuda ◽

Naohisa Yoshida ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

B Cell Lymphomas ◽

Additional Segment ◽

Large B Cell

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CD40L Modulates TRAIL-Induced Apoptosis in Germinal Center Derived B Cell Lymphomas.

Blood ◽

10.1182/blood.v108.11.4630.4630 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4630-4630

Author(s):

Marion Travert ◽

Patricia Ame-Thomas ◽

Thierry Fest ◽

Céline Pangault ◽

Gilbert Semana ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Cell Lines ◽

Germinal Center ◽

B Cell Lymphoma ◽

B Cell Lymphomas ◽

Lymphoma Cells ◽

Over Expression ◽

Induced Apoptosis ◽

Transformed Cell Lines

Abstract Follicular lymphoma are characterized by the rearrangement of the bcl-2 gene, present in more than 90% of patients. Over-expression of the bcl-2 protein resulting from this translocation is associated with the inability to eradicate the lymphoma, by inhibiting apoptosis. Despite the median survival ranges from 8 to 15 years, leading to the designation of indolent lymphoma, patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. Numerous reports have shown that Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in a wide variety of transformed cell lines of diverse lineage, but does not appear to kill normal cells, even though TRAIL mRNA is expressed at significant levels in most normal tissues. As cell death induced by TRAIL occurs almost exclusively in tumor cells, it suggests that this drug is safe to use as an antitumor therapy. We therefore investigated the efficiency of this cytokine to induce apoptosis in germinal center derived B cell lymphoma, despite bcl-2 over-expression. Our study was also designed to evaluate the role of CD40L, one of the main differentiation signal involved in B cell maturation during the germinal center reaction, on the regulation of TRAIL-induced apoptosis. This study was performed on three germinal center derived tumor cell lines (BL2, VAL and RL), and on normal and tumor primary cells obtained from human tonsils and lymph nodes. Our data show that normal B lymphocytes obtained from tonsil biopsies are resistant to TRAIL-mediated apoptosis, when B lymphoma cells issued from lymph node of numerous patients are significantly sensitive to the cytokine. When we treat these lymphoma cells with trimeric huCD40L, we partly rescue these cells from spontaneous apoptosis which naturally occurs after few days of culture, and reverse by 50% TRAIL-mediated apoptosis when cells were co-treated with huCD40L for 16 hours. Similar results were reproduced on some germinal center derived cell lines. BL2 was indeed found highly sensitive to TRAIL-induced apoptosis following a 24 hour exposure. On the opposite, VAL and RL were almost insensitive. We have demonstrate that apoptosis is exclusively mediated by TRAIL-R1 in BL2. Analysis of signalling pathways revealed that the protection to TRAIL-induced apoptosis by CD40L is due to some specific anti-apoptotic molecules that will be described. Genes encoding these molecules are targets of the NFκB signalling pathway activated by CD40L. Our results suggest that activation of NFκB and induction of anti-apoptotic molecules by CD40L play an important role in the protection of germinal center derived B cell lymphomas against apoptosis. Then, NFκB inhibitors may be wise to use in clinical trials in conjunction with TRAIL against follicular lymphomas.

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High expression of LMO2 in Hodgkin, Burkitt and germinal center diffuse large B cell lymphomas

Journal of the Egyptian National Cancer Institute ◽

10.1016/j.jnci.2011.10.006 ◽

2011 ◽

Vol 23 (4) ◽

pp. 147-153 ◽

Cited By ~ 2

Author(s):

Tahany M. Shams

Keyword(s):

B Cell ◽

Germinal Center ◽

High Expression ◽

B Cell Lymphomas ◽

Large B Cell

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Constitutively Activated STAT3 Promotes Cell Proliferation and Survival in the Activated B Cell Subtype of Diffuse Large B Cell Lymphomas.

Blood ◽

10.1182/blood.v110.11.1621.1621 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1621-1621

Author(s):

Bihui Hilda Ye ◽

Beibei Belinda Ding ◽

Jian Jessica Yu ◽

Raymond Y.-L. Yu ◽

Lourdes M. Mendez ◽

...

Keyword(s):

Cell Proliferation ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

B Cell Lymphoma ◽

Cell Development ◽

B Cell Development ◽

Reciprocal Relationship ◽

B Cell Lymphomas ◽

Large B Cell

Abstract During B cell development, cell proliferation and survival are regulated by stage-specific transcription factors. Accordingly, distinct oncogenic pathways are employed by B cell lymphomas representing different stages of B cell development. Diffuse large B cell lymphoma (DLBCL) contains at least two main phenotypic subtypes, i.e. the germinal center B cell-like (GCB-DLBCL) and the activated B cell-like (ABC-DLBCL) groups. It has been shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis. In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated NF-kappaB and tends to be refractory to chemotherapy. In this study, we investigated the relationship between BCL6 and STAT3 expression/activation in DLBCL and normal GC B cells. Our results demonstrate that BCL6 directly inhibits transcription of the STAT3 gene by binding to two BCL6 sites in its 5′ regulatory region. As a result, high level STAT3 expression and activation are preferentially detected in ABC-DLBCL and BCL6-negative normal germinal center B cells. Specifically, in tonsillar GCs, STAT3 expression and activation is restricted to a previously uncharacterized subset of BCL6−Blimp-1− B cells in the apical light zone. The location and phenotype of these cells suggest that they are in the process of exiting the BCL6-directed GC program and transitioning to a plasma cell differentiation process governed by Blimp-1. The reciprocal relationship between BCL6 and STAT3 is also conserved in DLBCL such that STAT3 expression and activation is preferentially associated with the BCL6-low, ABC subtype. Most importantly, inactivating STAT3 by either AG490 or small interference RNA in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis. These phenotypes are accompanied by decreased expression of several known STAT3 target genes, including c-Myc, JunB and Mcl-1, and increased expression of the cell cycle inhibitor p27. In addition to identifying STAT3 as a novel BCL6 target gene, our results define STAT3 activation as a second oncogenic pathway operating in ABC-DLBCL and suggest that blocking STAT3 may be potentially therapeutic in treatment of these aggressive lymphomas.

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BCL6 modulates tonic BCR signaling in diffuse large B-cell lymphomas by repressing the SYK phosphatase, PTPROt

Blood ◽

10.1182/blood-2009-02-204362 ◽

2009 ◽

Vol 114 (26) ◽

pp. 5315-5321 ◽

Cited By ~ 44

Author(s):

Przemyslaw Juszczynski ◽

Linfeng Chen ◽

Evan O'Donnell ◽

Jose M. Polo ◽

Stella M. Ranuncolo ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Transcriptional Repression ◽

Tyrosine Phosphatase ◽

Adaptor Protein ◽

B Cell Lymphomas ◽

Primary Tumors ◽

Bcr Signaling ◽

Large B Cell

Abstract Tonic B-cell receptor (BCR) signaling is a key survival pathway during normal B-cell ontogenesis and in a subset of diffuse large B-cell lymphomas (DLBCLs). We previously demonstrated that BCR-dependent DLBCL cell lines and primary tumors underwent apoptosis after treatment with an ATP-competitive inhibitor of the BCR-associated spleen tyrosine kinase (SYK). These “BCR-type” tumors also have more abundant expression of the transcriptional repressor, BCL6, and increased sensitivity to BCL6 inhibition. Herein, we evaluated potential connections between BCL6-mediated transcriptional repression and SYK-dependent BCR signaling. In transcriptionally profiled normal B-cell subsets (naive, germinal center, and memory B cells) and in primary DLBCLs, there were reciprocal patterns of expression of BCL6 and the SYK tyrosine phosphatase PTPROt. BCL6 repressed PTPROt transcription via a direct interaction with functional BCL6 binding sites in the PTPROt promoter. Enforced expression of BCL6 in normal naive B cells and RNAi-mediated depletion of BCL6 in germinal center B cells directly modulated PTPROt expression. In “BCR-type” DLBCLs, BCL6 depletion increased PTPROt expression and decreased phosphorylation of SYK and the downstream adaptor protein BLNK. Because BCL6 augments BCR signaling and BCL6 and SYK are both promising therapeutic targets in many DLBCLs, combined inhibition of these functionally related pathways warrants further study.

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