scholarly journals Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma

2020 ◽  
Vol 218 (3) ◽  
Author(s):  
Raud Razzaghi ◽  
Shreya Agarwal ◽  
Nikita Kotlov ◽  
Olga Plotnikova ◽  
Krystle Nomie ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Fas Ligand ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Interaction ◽  
Follicular Helper ◽  
Large B Cell Lymphoma ◽  
Aggressive Subtype

Fas is highly expressed on germinal center (GC) B cells, and mutations of FAS have been reported in diffuse large B cell lymphoma (DLBCL). Although GC-derived DLBCL has better overall outcomes than other DLBCL types, some cases are refractory, and the molecular basis for this is often unknown. We show that Fas is a strong cell-intrinsic regulator of GC B cells that promotes cell death in the light zone, likely via T follicular helper (Tfh) cell–derived Fas ligand. In the absence of Fas, GCs were more clonally diverse due to an accumulation of cells that did not demonstrably bind antigen. FAS alterations occurred most commonly in GC-derived DLBCL, were associated with inferior outcomes and an enrichment of Tfh cells, and co-occurred with deficiency in HVEM and PD-L1 that regulate the Tfh–B cell interaction. This work shows that Fas is critically required for GC homeostasis and suggests that loss of Tfh-mediated counterselection in the GC contributes to lethality in GC-derived lymphoma.

Preferential Acquision of N-Glycosylation Sites in the VDJ Region in Germinal Center B-Cell-Like Difusse Large B-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1589-1589 ◽  
Author(s):  
Miguel Alcoceba ◽  
Elena Sebastián ◽  
Ana Balanzategui ◽  
Luis Marín ◽  
Santiago Montes-Moreno ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Large B Cell Lymphoma ◽  
Glycosylation Sites ◽  
Large B Cell

Abstract Abstract 1589 Introduction: Acquired potentially N-glycosylation sites are produced by somatic hypermutation (SHM) in the immunoglobulin (Ig) variable region. This phenomenon is produced in ∼9% of normal B-cells and seems to be related to certain B-cell lymphoproliferative disorders (B-LPDs) such as follicular lymphoma (FL, 79%), endemic Burkitt lymphoma (BL, 82%) and diffuse large B-cell lymphoma (DLBCL, 41%). These data suggest that new potential N-glycosylation sites could be related to germinal center B (GCB)-LPDs. By contrast, in other B-LPDs, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), MALT lymphoma, Waldenström macroglobulinemia (WM) or multiple myeloma (MM), these modifications have not been analyzed in deep. Aims: To evaluate the acquisition of potential N-glycosylation sites in B-LPDs, including immunohystochemical DLBCL subtypes (GCB and non-GCB) and specific non-GCB-LPDs, such as hairy cell leukemia (HCL), splenic marginal-zone lymphoma (SMZL), CLL, MCL, ocular extranodal marginal zone lymphoma (OAEMZL), MM and WM. Patients: A total of 953 sequences (203 from our group and 750 previously published sequences) of B-LPDs were included. Diagnosis distribution was as follows: DLBCL (n=235), MCL (n=235), CLL (n=166), MM (n=96), OAEMZL (n=82), SMZL (n=68), WM (n=38) and HCL (n=33). Methods: Acquired N-glycosylation sites were counted according to the sequence Asn-X-Ser/Thr, where X could be any amino acid except Pro. Natural motifs in germline sequences of IGHV1–08, IGHV4–34 e IGHV-5a were not considered. Fisher test was used to perform comparisons between groups. To distinguish DLBCL biological subtypes (GCB and non-GCB DLBCL), Hans' algorithm was used. Results: A total of 83 out of the 235 DLBCL cases acquired at least a new N-glycosylation site, a higher value than in normal B-cells (35% vs. 9%, p<0.0001). Higher incidence of these motifs in the group of GCB as compared to non-GCB DLBCL were observed (52% vs. 20%, p<0.0001). Those cases diagnosed of HCL, CLL, MCL, MM, WM, OAEMZL and SMZL presented a reduced number of new N-glycosylation sites, showing similar values than normal B-cells (range 3–18%, p=ns). Conclusions: We described for the first time the pattern of N-glycosylation in HCL, SMZL, OAEMZL and in the immunohystochemical DLBCL subtypes, where the GCB-DLBCL showed a higher number of new N-glycosylation sites with respect to non-GCB DLBCL and other non-GCB-LPDs. The presence of novel N-glycosylation sites in FL, BL and in GCB-DLBCL strongly suggests that these motifs are characteristic of the germinal center B-LPDs. Disclosures: No relevant conflicts of interest to declare.

Fas and Fas ligand expression on germinal center type-diffuse large B-cell lymphoma is associated with the clinical outcome

2006 ◽  
Vol 76 (6) ◽  
pp. 465-472 ◽  
Author(s):  
Yasushi Kojima ◽  
Hisashi Tsurumi ◽  
Naoe Goto ◽  
Masahito Shimizu ◽  
Senji Kasahara ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Germinal Center ◽  
Fas Ligand ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Ligand Expression ◽  
Large B Cell

Fas or Fas Ligand Expression Can Determine the Clinical Outcome of Germinal Center Type in Diffuse Large B Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3267-3267
Author(s):  
Yasushi Kojima ◽  
Hisashi Tsurumi ◽  
Naoe Goto ◽  
Michio Sawada ◽  
Toshiki Yamada ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Germinal Center ◽  
Fas Ligand ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Significant Difference ◽  
Type 3 ◽  
Large B Cell

Abstract In recent years, diffuse large B cell lymphoma (DLBCL) has been classified by a cDNA microarray, an oligonucreotide microarray, or a tissue microarray. From the prognostic point of view, DLBCL consists of germinal center B-cell-like (GC) type, activated B-cell-like (ABC) type and type 3. ABC type and type 3 can be collectively categorized as non-GC (NGC) type. GC type has favorable prognosis compared with NGC type. Escape from apoptosis is considered to be an important mechanism for the progression of lymphoma. Fas is the major protein which leads to apoptosis by binding with Fas-ligand (FasL). We evaluated the prognostic significance of such markers as CD10, Bcl-6, MUM1, Fas and FasL, as well as GC or NGC type with paraffin embedded sections from 69 DLBCL patients immunohistochemicaly. The patients were 40 men and 29 women with median age of 67 years old (range, 20–82 years old). The median follow-up of surviving patients was 43 months. The 3-year OS for the entire group was 56%. There was no significant difference in sex, age, clinical stage, lactate dehydrogenase, or International Prognostic Index between GC and NGC type. Expression of CD10 was seen in 29% (20 of 69 of the patients), Bcl-6 in 27% (19 of 69), MUM1 in 27% (19 of 69), Fas in 51% (36 of 69), and FasL in 50% (35 of 69). We divided 69 DLBCLs to 26 GC type (CD10 positive or Bcl-6 positive and MUM1 negative) and 43 NGC type (the other). Positive CD10 was the best marker to indicate favorable overall survival (p=0.0156). GC type had tendency to have better overall survival than NGC type, though it was not significant (p=0.0723). Although Fas or FasL expression was not significant for overall survival in all DLBCL, it predicted significantly a longer over all survival (Fas; p=0.0021, FasL; p=0.0165) in GC type. These results may suggest that the presence of a subtype of DLBCL in which Fas/FasL system works effectively. This group is approximately 20% of DLBCL and mainly belongs to the GC type. Fas expression in GC type of DLBCL may predict the prognosis and be useful to choose the appropriate therapy. Furthermore, CD10 was more significant than GC type and, thus, we may need to build the strict consensus for GC type.

UCH-L1 Cooperates with BCL6 and Identifies Patients with Aggressive Germinal Center Diffuse Large B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2673-2673
Author(s):  
Tibor Bedekovics ◽  
Sajjad Hussain ◽  
Andrew L Feldman ◽  
Paul J. Galardy
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Substantial Impact ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Germinal Center B Cells

Abstract Gene expression profiling has identified two major subclasses of diffuse large B-cell lymphoma. Cases resembling germinal center B-cells (GCB-DLBCL) generally occur in younger patients, have a distinct molecular pathophysiology, and have improved outcomes compared with those similar to activated post-germinal center cells (ABC-DLBCL). We previously found that the ubiquitin hydrolase UCH-L1 is frequently overexpressed in mature B-cell malignancies and is a potent oncogene in mice. The cause for its overexpression in lymphoma, and whether it impacts the outcome of patients with DLBCL is unknown. Here we show that UCH-L1 reflects germinal center lineage in lymphoma and is an oncogenic biomarker of aggressive GCB-DLBCL. We find that UCH-L1 is specifically induced in germinal center B-cells in mice and humans, and that its expression correlates highly with the GCB subtype in DLBCL. Despite the typically good outcomes of GCB-DLBCL, increased UCHL1 identifies a subgroup with early relapses independent of MYC expression, suggesting biologic diversity in this subset of disease. We also find that UCH-L1 synergizes with BCL6 in a mouse model of germinal center B-cell lymphoma, but not with the development of multiple myeloma derived from post-germinal center cells. Consistent with this, forced Uchl1 overexpression had a substantial impact on gene expression in germinal center B-cells including pathways of cell cycle progression, cell death and proliferation, and DNA replication. These data demonstrate a novel role for UCH-L1 outside of the nervous system and suggest its potential use as a biomarker and therapeutic target in DLBCL. Disclosures Galardy: Mission Therapeutics: Research Funding.

scholarly journals Long-Term Survival and Gradual Recovery of B Cells in Patients (Pts) with Refractory Large B Cell Lymphoma (LBCL) Treated with Axicabtagene Ciloleucel (Axi-Cel)

2021 ◽  
Vol 27 (3) ◽  
pp. S404-S405
Author(s):  
Caron A. Jacobson ◽  
Frederick L. Locke ◽  
Armin Ghobadi ◽  
David B. Miklos ◽  
Lazaros J. Lekakis ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Term Survival ◽  
Long Term Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma

Blood ◽  
2016 ◽  
Vol 128 (2) ◽  
pp. 239-248 ◽  
Author(s):  
Julie Marie Matthews ◽  
Shruti Bhatt ◽  
Matthew P. Patricelli ◽  
Tyzoon K. Nomanbhoy ◽  
Xiaoyu Jiang ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Therapeutic Targeting ◽  
Large B Cell Lymphoma ◽  
Key Points ◽  
Large B Cell

Key Points GCK signaling is activated in DLBCL, and this signaling is important to DLBCL proliferation and survival. Therapeutic targeting of GCK is feasible and may advance efforts to cure DLBCL patients.

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