scholarly journals Multiple Omics Analysis Reveals E2F5 Predict Prognostic Biomarker in Diffuse Large B-Cell Lymphoma

2021 ◽  
Author(s):  
Jinshui Tan ◽  
Mengya Zhong ◽  
Qinwei Chen ◽  
Zhen Lu ◽  
Jie Zha ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cell ◽  
Mrna Expression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mitotic Cell ◽  
Transcription Analysis ◽  
Lower Survival Rate ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is highly aggressive and fatal hematological malignancy. There are few biomarkers that can be used to predict the survival of DLBCL patients. Therefore, there is an urgent need to find new biological targets to improve the predictive value and sensitive diagnosis of DLBCL.E2F family play an essential role in tumorigenesis, however, remains obscure in DLBCL.E2F transcription factor family(E2Fs) mRNA expression between DLBCL and nonmalignant samples were screened by GEPIA,CCLE and EMBL-EBI. The associated regulation pathway in DLBLC was established using the GeneMANIA,Metascape ,SMATAPP database. Transcription analysis indicated E2F1/4/5/8 mRNA expression was significantly higher in patients and the cell lines.What’s more, the high E2F5/8 expression had significantly lower survival rate. Further functional analysis showed that E2F1/3/5 were hypomethylated in DLBCL,which may associated with patient chemo-resistance. Subsequently,these genes with their co-expression genes mainly formed transcription factor complex, regulated G1/S transition of mitotic cell cycle and through TGF-beta signaling pathway to participate DLBCL tumorigenesis. This results demonstrate that E2F5 were potential prognostic biomarkers for better survival of DLBCL patients.

scholarly journals Biological Role of Transcription Factor Twist1 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

2018 ◽  
Vol 4 (2) ◽  
Author(s):  
Szablewski Vanessa ◽  
Merindol Natacha ◽  
Ballazin Sophie ◽  
Costes-Martineau Valérie ◽  
Bonnefoy Nathalie
Keyword(s):  
Transcription Factor ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Biological Role ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 945-951 ◽  
Author(s):  
Izidore S. Lossos ◽  
Carol D. Jones ◽  
Roger Warnke ◽  
Yasodha Natkunam ◽  
Herbert Kaizer ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Mrna Expression ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is characterized by a marked degree of morphologic and clinical heterogeneity. Establishment of parameters that can predict outcome could help to identify patients who may benefit from risk-adjusted therapies. BCL-6 is a proto-oncogene commonly implicated in DLBCL pathogenesis. A real-time reverse transcription–polymerase chain reaction assay was established for accurate and reproducible determination of BCL-6 mRNA expression. The method was applied to evaluate the prognostic significance ofBCL-6 expression in DLBCL. BCL-6 mRNA expression was assessed in tumor specimens obtained at the time of diagnosis from 22 patients with primary DLBCL. All patients were subsequently treated with anthracycline-based chemotherapy regimens. These patients could be divided into 2 DLBCL subgroups, one with high BCL-6 gene expression whose median overall survival (OS) time was 171 months and the other with low BCL-6 gene expression whose median OS was 24 months (P = .007). BCL-6 gene expression also predicted OS in an independent validation set of 39 patients with primary DLBCL (P = .01). BCL-6 protein expression, assessed by immunohistochemistry, also predicted longer OS in patients with DLBCL. BCL-6 gene expression was an independent survival predicting factor in multivariate analysis together with the elements of the International Prognostic Index (IPI) (P = .038). By contrast, the aggregate IPI score did not add further prognostic information to the patients' stratification byBCL-6 gene expression. High BCL-6 mRNA expression should be considered a new favorable prognostic factor in DLBCL and should be used in the stratification and the design of risk-adjusted therapies for patients with DLBCL.

Alteration of RhoH Expression Is Associated with Human Diffuse Large B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4298-4298
Author(s):  
Yi Gu ◽  
Carmelita J. Alvares ◽  
Aparna C. Jasti ◽  
Michael Jansen ◽  
Judy Bean ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cell ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
Binding Protein ◽  
B Cell Lymphoma ◽  
Cell Development ◽  
Transcript Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract An increasing number of Rho GTPase family proteins have been demonstrated to play critical roles in blood and immune cell development and function. The newly defined RhoH gene has been previously demonstrated to be mutated in lymphoma samples (Dallery et al, 1995; Pasqualucci et al, 2001). These alterations include chromosomal rearrangements and a high frequency of somatic mutations (up to 46%) in human non-Hodgkin’s lymphomas and diffuse large B-cell lymphoma. The RhoH gene encodes a novel hematopoietic-specific member of the RhoE subfamily, which is GTPase deficient, remaining in the active, GTP-bound state. Thus the activity of RhoH is likely regulated by the level of the protein expressed in the cell. The somatic mutations in the RhoH gene have been mapped to a 1.6kb hypermutable region in the intron 1, suggesting the possibility of dysregulated RhoH expression. However, levels of RhoH expression have not been directly measured in these hematopoietic tumors and so it remains unclear whether these mutations translate into aberrant RhoH expression. We utilized quantitative real-time RT-PCR to measure RhoH transcript levels in primary DLBCL patient samples. Based on morphologic and immunophenotypic analysis, 17 DLBCL positive samples and 14 normal control samples were used for our study. The levels of TATA-box binding protein (TBP) and human phosphogycerate kinase (HPGK) cDNAs were also examined simultaneously for relative expression normalization. RhoH transcript levels in a subset of the DLBCL samples were markedly reduced. In particular, 6 of 17 (~35%) tested samples showed a greater than 3-fold reduction in RhoH expression based on both RhoH/TBP and RhoH/HPGK ratios when compared with the median RhoH expression level of 14 normal samples. Overall, RhoH expression levels of the DLBCL group were significantly altered (mainly decreased) as compared with those of the normal group (p < 0.04, student T-test). To further determine correlation of the abnormal RhoH expression with somatic mutations in the hypermutable region of the RhoH gene in the DLBCL samples, we performed genomic PCR amplification and sequencing analysis of this region from the normal and DLBCL samples. In addition, we utilized a computational approach (Trafac - http://trafac.cchmc.org) to identify evolutionarily conserved putative transcription factor binding sites (TFBS) between human and other species in the hypermutable region. 13 conserved TFBS between human and mouse were identified in the hypermutable region. Mutations in the DLBCL patients are localized in 6 of these predicted TFBS, including pancreatic and duodenal homeobox 1 (PDX1), zinc-finger binding protein-89 (ZBP-89), lymphoid enhancer factor 1 (LEF-1), BRIGHT, engrailed 1 and myelin transcription factor 1 (MyT1). Interestingly, LEF-1 and BRIGHT are B cell-specific transcription activators. These results suggest that RhoH expression is frequently altered in 35–40% of DLBCL samples and mutations in the hypermutable region of the RhoH gene in several cases encompass core binding sequences of transcription factors important in B cell development.

CD30 Expression in Diffuse Large B-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1558-1558 ◽  
Author(s):  
Graham W. Slack ◽  
Christian Steidl ◽  
Laurie H. Sehn ◽  
Randy D. Gascoyne
Keyword(s):  
B Cell ◽  
Mrna Expression ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Independent Predictor ◽  
B Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
Genetics Research ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 1558 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with a variable clinical course. The addition of rituximab (R) to CHOP combination chemotherapy has improved overall (OS) and progression free survival (PFS) but some patients progress despite treatment and alternative therapies are needed. Brentuximab vedotin is an antibody-drug conjugate that targets CD30. It is efficacious in the treatment of relapsed Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma, two lymphomas associated with CD30 expression. The association between DLBCL and CD30 expression has not been well described. The aim of this study was to examine CD30 expression in DLBCL. Design: 395 cases of formalin-fixed paraffin-embedded DLBCL (excluding PMBCL) in a tissue microarray were independently evaluated by two pathologists for expression of CD30, CD10, BCL6, and MUM1 by immunohistochemistry (IHC) and EBV RNA (EBER) by in situ hybridization. CD30 expression was correlated with cell of origin (COO) phenotype, OS and PFS, EBV infection, International Prognostic Index (IPI) score and CD30 mRNA expression. The COO phenotype, germinal center B-cell like (GCB) or non-GCB, was determined by IHC using the Hans algorithm. CD30 mRNA expression and COO genotype by gene expression profiling (GEP) were determined using Affymetrix U133 2.0 Plus arrays (n=170). Outcome analysis only included patients treated with R-CHOP chemotherapy. CD30 was considered positive by IHC if any malignant cells exhibited membranous staining. The threshold for calling higher CD30 expression by GEP was determined using X-Tile software. Results: 25% (95/385) of DLBCL cases expressed CD30 by IHC with excellent concordance between two observers (r = 0.94). CD30 expression trended towards a non-GCB phenotype but was not significantly different (p=0.067). CD30 expression was not associated with PFS or OS in all R-CHOP treated cases (n=313); however, it was associated with a prolonged PFS in GCB-DLBCL (n=147) (p=0.019). In GCB-DLBCL CD30 expression remained an independent predictor of PFS in a multivariate analysis with IPI (p=0.038). CD30 expression by IHC was significantly associated with higher levels of CD30 mRNA (p=0.002). ABC-DLBCL exhibited significantly higher expression levels of CD30 mRNA (p=0.037). Higher CD30 mRNA expression was associated with a prolonged PFS in all R-CHOP treated DLBCL (p=0.012) as well as in DLBCL with a GCB-genotype (p=0.008), but not ABC or U-genotypes. Higher CD30 mRNA expression was also associated with a prolonged OS in the GCB-genotype (p=0.022). In the GCB-genotype higher CD30 mRNA expression remained an independent predictor of PFS, but not OS, in a multivariate analysis with IPI (p=0.037). EBV was identified in 3% of DLBCL (11/391), all of which exhibited a non-GCB phenotype (p=0.001) and were almost exclusively positive for CD30 expression (10/11)(p=<0.001). Conclusions: CD30 is expressed in approximately 25% of DLBCL and brentuximab vedotin could be considered for study in combination with traditional front-line therapies or as an alternative therapy in the relapsed or refractory disease. CD30 immunohistochemistry may be useful as a prognostic marker in R-CHOP treated GCB-DLBCL and the significant association of CD30 with EBV-positive non-GCB DLBCL suggests a distinct pathobiology for these cases. Disclosures: Slack: Seattle Genetics: Research Funding. Steidl:Seattle Genetics: Research Funding. Gascoyne:Seattle Genetics: Research Funding.

scholarly journals PD-L1 Expression Is Low in Large B-Cell Lymphoma with MYC or Double-Hit Translocation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4113-4113 ◽  
Author(s):  
Mette Vestergaard Elbæk ◽  
Mette Ø Pedersen ◽  
Marie Fredslund Breinholt ◽  
Anupama Reddy ◽  
Cassandra Love ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Mrna Expression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tissue Samples ◽  
Large B Cell Lymphoma ◽  
L1 Protein ◽  
Mrna Expression Levels ◽  
Large B Cell

Abstract Introduction: In large B-cell lymphoma (LBCL) MYC translocation and MYC/BCL2 or BCL6 double hit (DH) is associated with poor prognosis and there is an unmet need for novel treatment targets in this patient group. Treatment targeting the PD-L1/PD-1 pathway has been successfully introduced in Hodgkin lymphoma and solid cancers but are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. Material and Methods: MYC, BCL2 and BCL6 translocations were detected by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 patients had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. 24 patients overlapped, i.e. were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. Results: PD-L1 protein expression level was lower in patients with MYC translocation (n=42, median=3,3%, IQR 0,0-10,8) or DH (n=31, median=3,3%, IQR 0,0-10,0) compared to patients with no MYC translocation (n=35, median=16,7%, IQR 3,3-30,0) or DH (n=46, 13,3%, IQR 2,5-30,0), P=0.004 and P<0,001 respectively (Fig.1). PD-L1 mRNA expression was also significantly lower in patients with MYC translocation or DH, P=0,001 and P=0,006 respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-GC-type compared to GC-type DLBCL, P= 0,004 and P=0,002 respectively. Conclusions: We report a highly significant association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared to patients without these translocations. This should be evaluated in larger, prospective, consecutive trials. Disclosures No relevant conflicts of interest to declare.

Biological Significance of the Immumoproteasome Subunits Mecl-1 and LMP-2 in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2717-2717
Author(s):  
Lan V Pham ◽  
Alex Rollo ◽  
Archito T. Tamayo ◽  
John Lee ◽  
Zhuang Zuo ◽  
...  
Keyword(s):  
B Cell ◽  
Mrna Expression ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Biological Significance ◽  
B Cell Lymphoma ◽  
Proteasome Activity ◽  
Major Advance ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 2717 The biological significance of the ubiquitin-proteasome system in the control of cellular processes has been well-recognized; however, the pathophysiological importance of the immunoproteasome, the inducible form of the proteasome, has not been well-appreciated in cancer cells, particularly in this common diffuse large B-cell lymphoma (DLBCL), a clinically challenging, aggressive B-cell non-Hodgkin's lymphoma (NHL-B). The primary function of the immunoproteasome was originally believed to be only in immune cells to improve MHC-I antigen presentation efficiency in adaptive immune responses. It has now becomes evident that the immunoproteasome possesses broader biological functions, and is associated with various types of cancer. Using the Oncomine database to analyze the mRNA expression levels of immunoproteasome subunits in DLBCL, we found that the subunits MECL-1 and LMP-2 are highly expressed in comparison to normal B lymphocytes. We then examined the clinical significance of MECL-1 and LMP-2 mRNA expression in primary DLBCL, and found that increased MECL-1 mRNA expression is significantly associated with decreased cumulative overall survival rate (P=0.019). We then analyzed the protein expressions of MECL-1 and LMP-2 in various (20) DLBCL cell lines, and discovered that most of the DLBCL cell lines highly expressed both MECL-1 and LMP-2 but there is a subset of cell lines that did not express MECL-1 and LMP-2. Further analysis indicated that MECL-1 and LMP-2 subunits of the immunoproteasome are not associated with constitutive NF-kB activation in DLBCL since MECL-1 and LMP-2-negative DLBCL cell lines also express constitutive NF-kB activation. RNA interference-mediated knock-down of MECL-1 or LMP-2 leads to cell growth inhibition in DLBCL cell lines in vitro. These results strongly suggest that the immunoproteasome has important biological function in controlling growth and survival mechanisms in DLBCL and thus selective targeting of the immunoproteasome may offer therapeutic opportunity for this deadly disease. Bortezomib (BZ) is the first in the class of proteasome inhibitor (PSI) and represents a major advance in NHL, particularly mantle cell lymphoma. However, with the emergence of a new class of PSIs, such as Carfilzomib (CFZ), we are presented with opportunities to improve patient care in relapsed/refractory NHL-B. To elucidate the role of proteasome inhibitors in DLBCL, we analyzed the effect of BZ and CFZ in our representative DLBCL cell lines. BZ and CFZ treatments in DLBCL cell lines (20) have shown strong responses, with IC50s in the low nM ranges (2–50 nM). We have shown that DLBCL cell lines lacking both MECL-1 and LMP-2 are more resistant to CFZ than DLBCL cell lines that have both MECL-1 and LMP-2. To investigate a potential CFZ resistance mechanism(s) in these cell lines, we measured the 20S proteasome activity and compared this activity to the CFZ sensitive DLBCL cell lines. The results indicated that DLBCL cells that are more sensitive to CFZ show higher immunoproteasomal activity. The immunoproteasome activity in the resistant DLBCL cell lines is comparable to the proteasome activity found in normal B cells. These results suggest that the immunoproteasome is deregulated in DLBCL and represents a potential target for therapy in personalized medicine. Our studies emphasize understanding the mechanisms responsible for abnormal proteasomal function in DLBCL, that are critical for establishing an etiologic link to chemo-resistance and the development of new specific therapies for DLBCL targeting defective proteolysis through the immunoproteasome. Disclosures: No relevant conflicts of interest to declare.

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