scholarly journals Genomic and Transcriptional Characterization of Primary Mediastinal Large B Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2398-2398
Author(s):  
Rebecca J Leeman-Neill ◽  
Devang Thakkar ◽  
Sarah L. Ondrejka ◽  
Eric D. Hsi ◽  
Amy Chadburn ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Research Funding ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dna And Rna ◽  
Large B Cell Lymphoma ◽  
Recurrent Mutations ◽  
Large B Cell

Abstract Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare non-Hodgkin lymphoma subtype that occurs predominantly in young adults, with an overall favorable prognosis. The cell of origin is presumed to be thymic medullary B-cells and the gene expression profile of PMBL is similar to classic Hodgkin lymphoma. Recent studies have begun unravelling the genomic alterations underlying PMBL. Frequent, recurrent mutations (e.g. B2M, TNFAIP3, SOCS1, STAT6, GNA13) have been reported, but most of the studies have analyzed a small number of cases. To gain further insights into disease biology, we recruited 63 cases of PMBL as part of the Atlas of Blood Cancer Genomes (ABC-G) initiative, a consortium consisting of 25 institutions. Methods: Formalin-fixed paraffin-embedded (FFPE) biopsies and clinical data were collected. All cases were subjected to centralized review by an experienced panel of hematopathologists to ensure accurate diagnosis. Whole-exome DNA and RNA sequencing was performed using the Illumina platform and the DNA and RNA reads aligned to the GRCh38 genome and transcriptome respectively. Exonic variants were filtered using a set of paired normal samples and population-based databases to identify putative driver mutations, which were then aggregated at the gene level. Mutational analysis was performed on 56 samples that passed quality filtering and expression analysis on 45 samples. RNAseq data was normalized using DESeq2. Results: The cohort included samples from 16 males and 24 females, with a median age of 33 years (range 16 - 72) at the time of diagnosis. The majority of patients were treated with R-CHOP (47%) or R-EPOCH (43%), with 93% of patients surviving through the end of follow-up (median follow-up: 60.1 months). Besides the known recurrent mutations involving the JAK-STAT (STAT6 -21%, SOCS1 - 26%), NFKB (TNFAIP3 - 27%, NFKB1A - 7%), immune escape (B2M - 20%, LTB - 11%, IRF8 - 9%, IRF4 -9%), and chromatin modification (ZNF217 - 16%, CREBBP - 11%, KMT2D -11%) pathways , we discovered recurrent somatic variants in novel candidate driver genes in this disease, including NOTCH4 (7%), DICER1 (11%), MCL1 (7%), amongst others. EZH2, EP300, and XPO1 mutations were not detected. CIITA mutations and fusions were observed in 14% and 11% of cases, respectively, with novel partner genes (IGHA2, IGHG1, CDC6) detected in 67% of the fusion positive cases. Copy number alterations included gains at 2p16.1 (REL - 20%) and 9p24.2 (JAK2/PDL1/PDL2 - 24%), as well as loci not previously implicated in PMBL, 8q24.3 and 9q34.3 (each in 20%). Of note, CIITA alterations and 9p24 gains were virtually mutually exclusive, highlighting diverse mechanisms of immune escape in this entity. The transcriptomes of cases harboring CIITA alterations demonstrated differential enrichment of genes involved in protein glycosylation. The PMBLs in our series showed significant enrichment of the reported PMBL genetic classifier score, compared to nodal diffuse large B cell lymphoma (DLBCL) (p=0.0003). Finally, the gene expression profile of thymic B cells was more similar to that of PMBL than nodal DLBCL (p=0.0144). Conclusions: Our study, representing one of the largest comprehensive genomic and transcriptomic analyses of PMBL, expands the mutational landscape of PMBL, provides evidence for biologically distinct disease subsets and suggests an origin of PMBLs from thymic B-cells. Disclosures Hsi: AbbVie: Research Funding; Eli Lilly: Research Funding; Cytomx: Honoraria; Seattle Genetics: Honoraria. McKinney: BTG: Consultancy; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; Genetech: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Molecular Templates: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy; Verastem: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau. Jaye: Stemline Therapeutics: Honoraria. Cohen: Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding; Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

Spatial Signatures Identify Immune Escape via PD-1 as a Defining Feature of T-cell/Histiocyte-rich Large B-cell Lymphoma

Blood ◽  
2020 ◽  
Author(s):  
Gabriel K. Griffin ◽  
Jason L. Weirather ◽  
Margaretha Roemer ◽  
Mikel Lipschitz ◽  
Alyssa Kelley ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Spatially Resolved ◽  
Large B Cell Lymphoma ◽  
Immune Signatures ◽  
Large B Cell

T-cell/histiocyte-rich large B cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbor PD-L1/PD-L2 copy gain or amplification in 64% of cases, which is associated with increased PD-L1 expression (p = 0.0111). By directed and unsupervised spatial analyses of multi-parametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune 'neighborhoods' in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1-positive T cells. Further, unbiased clustering of spatially-resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in three of five patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies, including two complete responses and one partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL, and also support the potential utility of spatially-resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.

Epigenetic mechanisms of therapy resistance in diffuse large B cell lymphoma (DLBCL)

2021 ◽  
Vol 20 ◽  
Author(s):  
Yusuke Isshiki ◽  
Ari Melnick
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Immune Surveillance ◽  
B Cell Lymphoma ◽  
Therapy Resistance ◽  
Genetic Profiling ◽  
Large B Cell Lymphoma ◽  
Recurrent Mutations ◽  
Large B Cell

: Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin B cell lymphoma (NHL), and manifest highly heterogeneous genetic/phenotypic characteristics as well as variable responses to conventional immunochemotherapy (1). Genetic profiling of DLBCL patients has revealed highly recurrent mutations of epigenetic regulator genes such as CREBBP, KMT2D, EZH2 and TET2. These mutations drive malignant transformation by through aberrant epigenetic programming of B-cells and may influence clinical outcomes (2-4). These and other chromatin modifier genes also play critical roles in normal B-cells, as they undergo the various phenotypic transitions characteristic of the humoral immune response. Many of these functions have to do with impairing immune surveillance and may critically mediate resistance to immunotherapies. In this review, we describe how epigenetic dysfunction induces lymphomagenesis and discuss ways for implementing precision epigenetic therapies to reverse these immune resistant phenotypes.

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 Primary Type3 (Non-ABC, Non-GCB) Subtype of Extranodal Diffuse Large B-Cell Lymphoma of the Thyroid Bearing No MYD88 Mutation by Padlock Probe Hybridization

2017 ◽  
Vol 10 (2) ◽  
pp. 508-514 ◽  
Author(s):  
Yukiko Nishi ◽  
Riko Kitazawa ◽  
Ryuma Haraguchi ◽  
Ayaka Ouchi ◽  
Yasuo Ueda ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Malignant Lymphoma ◽  
Cell Lymphoma ◽  
Clinical Phenotype ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Japanese Female ◽  
Old Japanese ◽  
Large B Cell

Primary extranodal malignant lymphoma of the thyroid is a rare entity composed of mostly neoplastic transformation of germinal center-like B cells (GCB) or memory B cells. Other B-cell-type malignancies arising primarily in the thyroid have rarely been described. Immunohistochemical examination of autopsied primary malignant lymphoma of the thyroid in an 83-year-old Japanese female revealed the presence of a non-GCB subtype of diffuse large B-cell lymphoma (DLBCL) without the typical codon 206 or 265 missense mutation of MYD88. The lack of the highly oncogenic MYD88 gene mutation, frequently observed in DLBCL of the activated B-cell (ABC) subtype, and the detection of an extremely aggressive yet local clinical phenotype demonstrated that the present case was an exceptional entity of the type3 (non-GCB and non-ABC) subtype.

Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4503-4506 ◽  
Author(s):  
Anja Mottok ◽  
Christoph Renné ◽  
Marc Seifert ◽  
Elsie Oppermann ◽  
Wolf Bechstein ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Rare Mutations ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Follicular Lymphomas ◽  
Large B Cell

Abstract STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell–specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1. One-fourth of diffuse large B-cell lymphoma and follicular lymphomas carried SOCS1 mutations, which were preferentially targeted to SHM hotspot motifs and frequently obviously inactivating. Rare mutations were observed in Burkitt lymphoma, plasmacytoma, and mantle cell lymphoma but not in tumors of a non–B-cell origin. Mutations in single-sorted germinal center B cells were infrequent relative to other genes mutated as byproducts of normal SHM, indicating that SOCS1 inactivation in primary mediastinal large B-cell lymphoma, HL, diffuse large B-cell lymphoma, and follicular lymphoma is frequently the result of aberrant SHM.

scholarly journals Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 454-454 ◽  
Author(s):  
Yucai Wang ◽  
Umar Farooq ◽  
Brian K. Link ◽  
Mehrdad Hefazi ◽  
Cristine Allmer ◽  
...  
Keyword(s):  
B Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Newly Diagnosed ◽  
Indolent Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

scholarly journals PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell–inflamed phenotype

Blood ◽  
2019 ◽  
Vol 133 (21) ◽  
pp. 2279-2290 ◽  
Author(s):  
James Godfrey ◽  
Sravya Tumuluru ◽  
Riyue Bao ◽  
Michael Leukam ◽  
Girish Venkataraman ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Data Set ◽  
Large B Cell Lymphoma ◽  
Programmed Death ◽  
Large B Cell ◽  
Gene Alterations

Abstract Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copy-number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harboring PD-L1 gene alterations, thereby enabling a characterization of the immunogenomic landscape of these lymphomas. Among 105 DLBCL cases analyzed, PD-L1 alterations were identified in 27%. PD-L1 alterations were highly enriched among non–germinal center DLBCLs and exhibited robust PD-L1 protein expression. These lymphomas were heavily infiltrated by clonally restricted T cells and frequently downregulated human leukocyte antigen expression. RNA sequencing of PD-L1–altered DLBCLs revealed upregulation of genes involved in negative T-cell regulation and NF-κB pathway activation, while whole-exome sequencing identified frequent mutations in genes involved in antigen presentation and T-cell costimulation. Many of these findings were validated in a large external data set. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemoimmunotherapy; however, in the relapsed/refractory setting, PD-L1 alterations were associated with response to anti-PD-1 therapy. Collectively, our results indicate that PD-L1 alterations identify a unique biological subset of DLBCL in which an endogenous antilymphoma immune response has been activated, and that is associated with responsiveness to PD-1 blockade therapy.

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

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.

scholarly journals Analysis of FOXO1 mutations in diffuse large B-cell lymphoma

Blood ◽  
2013 ◽  
Vol 121 (18) ◽  
pp. 3666-3674 ◽  
Author(s):  
Diane L. Trinh ◽  
David W. Scott ◽  
Ryan D. Morin ◽  
Maria Mendez-Lago ◽  
Jianghong An ◽  
...  
Keyword(s):  
Dna Binding ◽  
B Cell ◽  
Cell Lymphoma ◽  
Phosphorylation Site ◽  
B Cell Lymphoma ◽  
Dna Binding Domain ◽  
Large B Cell Lymphoma ◽  
Key Points ◽  
Recurrent Mutations ◽  
Large B Cell

Key Points Recurrent mutations in FOXO1 affect the DNA binding domain and the T24 phosphorylation site, which disrupt interactions with 14-3-3. Presence of FOXO1 mutations is associated with decreased OS, particularly in DLBCL patients of the low-risk R-IPI categories.

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