A miR-129-5P/ARID3A Negative Feedback Loop Modulates Diffuse Large B Cell Lymphoma Progression and Immune Evasion Through Regulating the PD-1/PD-L1 Checkpoint

The activated B cell (ABC) and germinal center B cell (GCB) subtypes of diffuse large B cell lymphoma (DLBCL) have different gene expression profiles and clinical outcomes, and miRNAs have been reported to play important roles in tumorigenesis, progression, and metastasis. This study aimed to explore the differentially expressed miRNAs and target genes in the two main subtypes of DLBCL. Hub miRNAs were identified by constructing a regulatory network, and in vitro experiments and peripheral blood samples of DLBCL were used to explore the functions and mechanisms of differential miRNAs and mRNAs. Differentially expressed miRNAs and genes associated with the two DLBCL subtypes were identified using GEO datasets. Weighted gene co-expression network analysis shows that one gene module was associated with a better prognosis of patients with the GCB subtype. Through the construction of a regulatory network and qPCR verification of clinical samples and cell lines, miR-129-5p was identified as an important differential miRNA between the ABC and GCB subtypes. The negative relationship between miR-129-5p and ARID3A in DLBCL was confirmed using luciferase reporter assays. Overexpression of miR-129-5p and knockdown of ARID3A inhibited the proliferation of SU-DHL-2 (ABC-type) cells and promoted their apoptosis through the JAK and STAT6 signaling pathways. In addition, inhibition of miR-129-5p and overexpression of ARID3A promoted the proliferation and reduced apoptosis of DB and SU-DHL-6 (GCB-type) cells. Inhibition of miR-129-5p and overexpression of ARID3A in DB and SU-DHL-6 promoted immune escape by increasing PD-L1 expression, which was transcriptionally activated by ARID3A. In conclusion, we showed for the first time that the mir-129-5P/ARID3A negative feedback loop modulates DLBCL progression and immune evasion by regulating PD-1/PD-L1.

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LncRNA SNHG14/miR-5590-3p/ZEB1 positive feedback loop promoted diffuse large B cell lymphoma progression and immune evasion through regulating PD-1/PD-L1 checkpoint

Cell Death and Disease ◽

10.1038/s41419-019-1886-5 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 26

Author(s):

Lina Zhao ◽

Ye Liu ◽

Jingbo Zhang ◽

Yan Liu ◽

Qi Qi

Keyword(s):

B Cell ◽

Immune Evasion ◽

Feedback Loop ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Bioinformatics Tool ◽

Positive Feedback Loop ◽

Large B Cell Lymphoma ◽

Programmed Death ◽

Large B Cell

Abstract Diffuse large B cell lymphoma (DLBCL) is the commonest disorder derived from the B-lymphocytes. Inhibiting the immune checkpoint through naturalizing programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) is proved to be a successful therapeutic regime for lymphoma. Long non-coding RNAs (lncRNAs) are unceasingly reported to be promising biological targets for the cancer therapies. This study planned to explore the regulation of small nucleolar RNA host gene 14 (SNHG14) on DLBCL. SNHG14 level in DLBCL samples and cell lines was analyzed by GEPIA bioinformatics tool and RT-qPCR. Biological functions of SNHG14 in DLBCL were detected by CCK-8, colony formation, and transwell invasion assays. Molecular interaction was determined by RNA immunoprecipitation (RIP) and luciferase reporter assays. MiR-5590-3p-related pathway was identified through KEGG pathway analysis applying DAVID6.8 online bioinformatics tool. Effect of SNHG14 on CD8+ T cells was detected by flow cytometry. Results depicted that SNHG14 was upregulated in DLBCL and its depletion retarded proliferation, migration and epithelial-to-mesenchymal transition (EMT). Mechanistically, SNHG14 sponged miR-5590-3p to upregulate Zinc finger E-box binding homeobox 1 (ZEB1), and ZEB1 transcriptionally activated SNHG14 and PD-L1 to promote the immune evasion of DLBCL cells. In conclusion, we firstly showed that SNHG14/miR-5590-3p/ZEB1 positive feedback loop promoted diffuse large B cell lymphoma progression and immune evasion through regulating PD-1/PD-L1 checkpoint, indicating that targeting SNHG14 was a potential approach to improve the efficacy of immunotherapy in DLBCL.

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lncRNA SNHG14 promotes oncogenesis and immune evasion in diffuse large-B-cell lymphoma by sequestering miR-152-3p

Leukemia & Lymphoma ◽

10.1080/10428194.2021.1876866 ◽

2021 ◽

pp. 1-15

Author(s):

Yuyang Tian ◽

Lianqiao Li ◽

Guoqiang Lin ◽

Yan Wang ◽

Li Wang ◽

...

Keyword(s):

B Cell ◽

Immune Evasion ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Epigenetic regulation of miR-518a-5p-CCR6 feedback loop promotes both proliferation and invasion in diffuse large B cell lymphoma

Epigenetics ◽

10.1080/15592294.2020.1786317 ◽

2020 ◽

pp. 1-17

Author(s):

Qian Huang ◽

Feng Zhang ◽

Haiying Fu ◽

Jianzhen Shen

Keyword(s):

B Cell ◽

Epigenetic Regulation ◽

Feedback Loop ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Proliferation And Invasion ◽

Large B Cell

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Understanding Immune Evasion and Therapeutic Targeting Associated with PD-1/PD-L1 Pathway in Diffuse Large B-cell Lymphoma

International Journal of Molecular Sciences ◽

10.3390/ijms20061326 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1326 ◽

Cited By ~ 10

Author(s):

Moo-Kon Song ◽

Byeong-Bae Park ◽

Jieun Uhm

Keyword(s):

Clinical Trials ◽

B Cell ◽

Immune Evasion ◽

Immune Checkpoint ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Targeting Therapy ◽

Large B Cell Lymphoma ◽

Programmed Death ◽

Large B Cell

In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin’s lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.

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Reconstruction of Canine Diffuse Large B-cell Lymphoma Gene Regulatory Network: Detection of Functional Modules and Hub Genes

Journal of Comparative Pathology ◽

10.1016/j.jcpa.2014.11.008 ◽

2015 ◽

Vol 152 (2-3) ◽

pp. 119-130 ◽

Cited By ~ 8

Author(s):

M. Zamani-Ahmadmahmudi ◽

A. Najafi ◽

S.M. Nassiri

Keyword(s):

B Cell ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Functional Modules ◽

Hub Genes ◽

Large B Cell Lymphoma ◽

Gene Regulatory ◽

Large B Cell

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Immune evasion-related extranodal large B-cell lymphoma: A report of six patients with neoplastic PD-L1-positive extranodal diffuse large B-cell lymphoma

Pathology International ◽

10.1111/pin.12742 ◽

2019 ◽

Vol 69 (1) ◽

pp. 13-20 ◽

Cited By ~ 8

Author(s):

Yuka Suzuki ◽

Ayako Sakakibara ◽

Kazuyuki Shimada ◽

Satoko Shimada ◽

Eri Ishikawa ◽

...

Keyword(s):

B Cell ◽

Immune Evasion ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Mutational Dynamics and Evolutionary Divergence in DLBCL: A Call for Relapse Sampling

Blood ◽

10.1182/blood-2019-131072 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1497-1497

Author(s):

Jillian F. Wise ◽

Sigve Nakken ◽

Chloé B Steen ◽

Daniel Vodák ◽

Gunhild Trøen ◽

...

Keyword(s):

B Cell ◽

Loss Of Heterozygosity ◽

Immune Evasion ◽

Research Funding ◽

Cell Lymphoma ◽

Clonal Evolution ◽

B Cell Lymphoma ◽

Driver Genes ◽

Large B Cell Lymphoma ◽

Large B Cell

Introduction Relapses of diffuse large B-cell lymphoma typically occur within 2-3 years and only 10% of these patients reach a 3-year progression-free survival compared to 65% at diagnosis. Our ability to distinguish patients at risk for relapse remains based on clinical staging. We hypothesized that identifying genetic alterations in serial tumour biopsies at diagnosis and relapse would improve our ability to identify high-risk patients, make therapeutic selections and reveal molecular markers for chemo-immunotherapy resistant tumours. However, relatively few relapsed/refractory biopsies have been sequenced. A unique, clinically annotated, Nordic DLBCL cohort was used to identify significantly mutated genes, assess potential driver genes, comprehensively examine clonal evolution, and gauge the importance of clinical relapsed sampling. Methods To address the lack of information on the molecular foundations of relapsed/refractory DLBCL, we performed whole exome sequencing (WES) on 42 DLBCL cases, with 34% representing relapsed/refractory biopsies and 13 serially sample cases. Enriched with relapsed/refractory diffuse large B-cell lymphoma cases, we performed multiple computational analyses to identify significantly mutated genes (MutSig2CV), mutational signatures (NMF and DeConstructsSig), driver genes (IntOgen and CADD), clonal evolution architecture (SciClone and ClonEvol), druggable gene analysis (DGIdb), and HLA-inference and mutation calling (Polysolver). Results Clonal evolution analysis of 13 paired diagnostic and relapsed biopsies revealed that relapsed/refractory biopsies have remarkable similarities to diagnostic biopsies and often present with late divergent clonal evolution of the tumor. Mutational analysis of 18 serially sampled tumors determined that in the majority of cases druggable oncogenic variants do arise at relapse. In addition, time to relapse correlated with divergence of mutations from the diagnostic biopsy. In addition to being identified as a significantly mutated gene, mutations in HLA-A had an increased incidence in cases that ultimately relapsed. This result led to an in-depth investigation into the mutational prevalence, timing, impact on prognosis, and loss of heterozygosity in the human leukocyte antigen (HLA) haplotypes of relapsed/refractory DLBCL. HLA-A mutagenesis and loss of heterozygosity was discovered as mechanisms of immune evasion in cases that go on to relapse from R-CHOP like therapies (Figure 1). Conclusions Our results yield insight into the development of chemo-immunotherapy resistant diffuse large B-cell lymphoma, and highlight the clinical importance of sampling relapsed biopsies. Analysis of immune evasion through MHC Class I/II, specifically HLA-A, may provide better characterization of patients for relapse prediction. In the age of personalized medicine it will be instrumental to determine if relapsed biopsies offer additional insight for salvage therapy treatment. Divergence of biopsies, as characterized by shared genomic mutations, increase with time and the majority of cases present with new alterations in druggable genes post-therapy. Disclosures Leppa: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Bayer: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board.

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Frequent Genetic Alterations in Immune Checkpoint-Related Genes in Intravascular Large B-Cell Lymphoma

Blood ◽

10.1182/blood.2020007245 ◽

2020 ◽

Author(s):

Kazuyuki Shimada ◽

Kenichi Yoshida ◽

Yasuhiro Suzuki ◽

Chisako Iriyama ◽

Yoshikage Inoue ◽

...

Keyword(s):

B Cell ◽

Immune Evasion ◽

Mononuclear Cells ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Genetic Alterations ◽

Unique Type ◽

Large B Cell Lymphoma ◽

Tumor Dna ◽

Large B Cell

Intravascular large-B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n = 18), patient-derived xenograft tumors (n = 4), and tumor DNA from bone marrow (BM) mononuclear cells (n = 3). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large-B-cell lymphoma (DLBCL) (P < 0.0001) and healthy donors (P = 0.0053), allowing us to perform WES, and most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated-B-cell-type DLBCL; with the former showing conspicuously higher frequencies (compared to nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 (38%) IVLBCL harbored rearrangements of PD-L1/PD-L2 involving the 3′-UTR; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL.

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