Value of PD-L1 Protein Expression in the Combined Prognostic Model of Diffuse Large B-Cell Lymphoma

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.

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Fluorescent nanoparticle‐mediated semiquantitative MYC protein expression analysis in morphologically diffuse large B‐cell lymphoma

Pathology International ◽

10.1111/pin.13131 ◽

2021 ◽

Author(s):

Natsuko Takayanagi ◽

Shuji Momose ◽

Jun Kikuchi ◽

Yuka Tanaka ◽

Tomoe Anan ◽

...

Keyword(s):

Protein Expression ◽

B Cell ◽

Expression Analysis ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Fluorescent Nanoparticle ◽

Large B Cell

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Loss of O 6 -Methylguanine-DNA Methyltransferase Protein Expression Is a Favorable Prognostic Marker in Diffuse Large B-Cell Lymphoma

International Journal of Hematology ◽

10.1532/ijh97.05182 ◽

2006 ◽

Vol 83 (4) ◽

pp. 341-347 ◽

Cited By ~ 16

Author(s):

Toshihito Ohno ◽

Junji Hiraga ◽

Haruhiko Ohashi ◽

Chiho Sugisaki ◽

Eika Li ◽

...

Keyword(s):

Protein Expression ◽

B Cell ◽

Prognostic Marker ◽

Dna Methyltransferase ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Methylguanine Dna Methyltransferase ◽

Large B Cell Lymphoma ◽

Large B Cell

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Central nervous system relapse in diffuse large B-cell lymphoma: analysis of risk factors and a new prognostic model

Annals of Oncology ◽

10.1093/annonc/mdv471.28 ◽

2015 ◽

Vol 26 ◽

pp. vii85

Author(s):

Yusuke Kanemasa ◽

Tatsu Shimoyama ◽

Yuki Sasaki ◽

Sawada Takeshi ◽

Eisaku Sasaki ◽

...

Keyword(s):

Risk Factors ◽

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Prognostic Model ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Central Nervous System Relapse ◽

Large B Cell Lymphoma ◽

Large B Cell

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Concurrent Expression of MYC and BCL2 in Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Journal of Clinical Oncology ◽

10.1200/jco.2011.41.0985 ◽

2012 ◽

Vol 30 (28) ◽

pp. 3452-3459 ◽

Cited By ~ 556

Author(s):

Nathalie A. Johnson ◽

Graham W. Slack ◽

Kerry J. Savage ◽

Joseph M. Connors ◽

Susana Ben-Neriah ◽

...

Keyword(s):

Protein Expression ◽

B Cell ◽

Cell Lymphoma ◽

Molecular Subtype ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Bcl2 Protein ◽

Large B Cell

Purpose Diffuse large B-cell lymphoma (DLBCL) is curable in 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MYC translocations, with or without BCL2 translocations, have been associated with inferior survival in DLBCL. We investigated whether expression of MYC protein, with or without BCL2 protein expression, could risk-stratify patients at diagnosis. Patients and Methods We determined the correlation between presence of MYC and BCL2 proteins by immunohistochemistry (IHC) with survival in two independent cohorts of patients with DLBCL treated with R-CHOP. We further determined if MYC protein expression correlated with high MYC mRNA and/or presence of MYC translocation. Results In the training cohort (n = 167), MYC and BCL2 proteins were detected in 29% and 44% of patients, respectively. Concurrent expression (MYC positive/BCL2 positive) was present in 21% of patients. MYC protein correlated with presence of high MYC mRNA and MYC translocation (both P < .001), but the latter was less frequent (both 11%). MYC protein expression was only associated with inferior overall and progression-free survival when BCL2 protein was coexpressed (P < .001). Importantly, the poor prognostic effect of MYC positive/BCL2 positive was validated in an independent cohort of 140 patients with DLBCL and remained significant (P < .05) after adjusting for presence of high-risk features in a multivariable model that included elevated international prognostic index score, activated B-cell molecular subtype, and presence of concurrent MYC and BCL2 translocations. Conclusion Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.

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C-MYC Protein Expression and High Ki-67 Proliferative Index are Predictives of Disease Relapse in Diffuse Large B Cell Lymphoma

Asian Pacific Journal of Cancer Biology ◽

10.31557/apjcb.2021.6.1.15-20 ◽

2021 ◽

Vol 6 (1) ◽

pp. 15-20

Author(s):

Mahmoud Tag El-Hussien ◽

Nadia Mokhtar ◽

Eman Naguib Khorshed

Keyword(s):

Protein Expression ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Statistical Prediction ◽

Proliferative Index ◽

Ki 67 ◽

Large B Cell Lymphoma ◽

Large B Cell

Objective: To evaluate the status of C-MYC protein expression and Ki-67 proliferative index and to clarify their role in predicting relapse of diffuse large B cell lymphoma (DLBL). Materials and Methods: A retrospective study conducted on 50 cases diagnosed as DLBL in a 3 years’ time period from January 2014 till December 2016, collected from the archive of Pathology Departments of the National Cancer Institute Cairo - Egypt, Misr University for Science and Technology and private labs of authors. The diagnosis of DLBL for all cases, both nodal and extranodal, was confirmed by histopathologic examination and immunophenotyping. Automated immunohistochemical staining using antibodies against C-MYC protein and MIB-1 was used to evaluate the C-MYC expression in tumor cells and to assess their proliferative ability by calculating Ki-67 labelling index. The relation between the percentage of C-MYC protein expression, Ki-67 proliferative index, clinical data and the relapse status during the follow up period were analyzed. Results: A total of 50 cases of DLBL in both nodal and extra-nodal sites were included. Twenty-three cases (46%) were expressing the C-MYC protein, and 29 cases (58%) showed high Ki-67 proliferative index. Twenty-two cases (44%) relapsed during the follow-up period. Positive C-MYC protein expression was significantly associated with high Ki-67 proliferative index. C-MYC protein expression and high Ki-67 proliferative index were independently associated with disease relapses in 81.8% and 86.4% of cases respectively. Cases with combined C-MYC protein expression and high Ki-67 proliferative index showed statistical prediction of relapse in 81.8% of cases. Conclusion: C-MYC protein expression and high Ki-67 proliferative index were independently associated with relapse of diffuse large B cell lymphoma. Furthermore, the combined positive C-MYC protein expression and high Ki-67 proliferative index is better than a single positive test in predicting relapses among DLBL patients.

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An NCCN-IPI based immune-related gene prognostic model for diffuse large B-cell lymphoma

10.1101/2021.03.03.433839 ◽

2021 ◽

Author(s):

Shidai Mu ◽

Deyao Shi ◽

Lisha Ai ◽

Fengjuan Fan ◽

Fei Peng ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Prognostic Model ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Risk Patients ◽

Large B Cell

AbstractBackgroundAn enhanced International Prognostic Index (NCCN-IPI) was built to better discriminate diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. However, there is an urgent need to identify novel valuable biomarkers in the context of targeted therapies, such as immune checkpoint blockade (ICB) therapy.MethodsGene expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. 73 immune-related hub genes in DLBCL patients with different IPI levels were identified by weighted gene co-expression network analysis (WGCNA), and 4 genes were selected to construct an IPI-based immune-related prognostic model (IPI-IPM). Afterward, the genetic, somatic mutational and molecular profiles of IPI-IPM subgroups were analyzed, as well as the potential clinical response of ICB in different IPI-IPM subgroups.ResultsThe IPI-IPM was constructed base on the expression of LCN2, CD5L, NLRP11 and SERPINB2, where high-risk patients had shorter overall survival (OS) than low-risk patients, consistent with the results in the GEO cohorts. The comprehensive results showed that a high IPI-IPM risk score was correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, high infiltration of CD8+ T cells and macrophages (M1, M2), as well as up-regulation of inhibitory immune checkpoints including PD-L1, LAG3 and BTLA, indicating more potential response to ICB therapy.ConclusionThe IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms on tumor progression and drug resistance, also sheds a light on developing immunotherapy for DLBCL.

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Low rather than high Ki-67 protein expression is an adverse prognostic factor in diffuse large B-cell lymphoma

Leukemia & Lymphoma ◽

10.1080/10428190802140055 ◽

2008 ◽

Vol 49 (8) ◽

pp. 1501-1509 ◽

Cited By ~ 21

Author(s):

Sverker Hasselblom ◽

Börje Ridell ◽

Margret Sigurdardottir ◽

Ulrika Hansson ◽

Herman Nilsson-Ehle ◽

...

Keyword(s):

Prognostic Factor ◽

Protein Expression ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Ki 67 ◽

Adverse Prognostic Factor ◽

Large B Cell Lymphoma ◽

Large B Cell

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A 70% cut-off for MYC protein expression in diffuse large B cell lymphoma identifies a high-risk group of patients

Haematologica ◽

10.3324/haematol.2019.235556 ◽

2020 ◽

Vol 105 (11) ◽

pp. 2667-2670 ◽

Cited By ~ 3

Author(s):

Marita Ziepert ◽

Stefano Lazzi ◽

Raffaella Santi ◽

Federica Vergoni ◽

Massimo Granai ◽

...

Keyword(s):

High Risk ◽

Protein Expression ◽

B Cell ◽

Cell Lymphoma ◽

Risk Group ◽

B Cell Lymphoma ◽

High Risk Group ◽

Large B Cell Lymphoma ◽

Large B Cell

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Effect of siRNA interference of ubiquitin-specific protease 9X on apoptosis and growth of diffuse large B cell lymphoma cell line

Materials Express ◽

10.1166/mex.2020.1653 ◽

2020 ◽

Vol 10 (3) ◽

pp. 446-453

Author(s):

Wei Peng ◽

Meizuo Zhong ◽

Youhong Tang

Keyword(s):

B Cells ◽

Protein Expression ◽

B Cell ◽

Cell Apoptosis ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Specific Protease ◽

Sirna Interference ◽

Large B Cell

Ubiquitin-specific protease 9X (USP9X) is crucial in the diagnosis and treatment of many tumor types, but its role in Diffuse Large B Cell Lymphoma (DLBCL) has not been determined. The current study aimed to examine the effects of RNA interference on USP9X expression, and subsequently on the bioactivity of DLBCL Farage and Pfeiffer cells. There were two groups in the study: USP9X-siRNA and NC. USP9X siRNA was transiently transferred into DLBCL cells by Cationic liposome. The total RNA was extracted using Fe2O3 and was retrieved into the DNA using the MagBeads Total RNA Extraction Kit. The protein expression of USP9X in Farage, Pfeiffer, and normal human B cell line at the cellular level was observed by Western blot. The Farage and Pfeiffer cells were infected with USP9X-siRNA. Cell apoptosis and cell growth viability were analyzed by flow cytometry and CCK8, Mcl-1 protein, a potential target of USP9X, and apoptosis factor proteins (such as Bak, Cytochrome C, Caspase 3, Caspase 8, PARP) were detected by Western blot after siRNA interference. The results showed that the protein expression of USP9X in malignant B cells was four times higher than that of the normal B cells. Inhibition of USP9X reduced the Mcl-1 activity, and increased the caspase-3, Bak and Cytochrome C activity. In the malignant B cells, Mcl-1 and Bak were binding in vivo; Bak was a new partner of Mcl-1. Inhibition of USP9X reduced cell proliferation and increased apoptosis. The expression of USP9X is upregulated in Diffuse large B cell lymphoma cells, Farage, and Pfeiffer. Inhibition expression of USP9X may induce cell apoptosis, inhibit cell growth, and downregulate Mcl-1 protein expression in Diffuse large B cell lymphoma cells, Farage, and Pfeiffer. USP9X has the ability in regulating cell apoptosis.

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