Positive Lymphoma Research Articles

A Case of Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma Occurring in Thyroid Gland

Epstein-Barr virus positive diffuse large B-cell lymphoma is very rare malignant tumor in thyroid gland. Compared to Epstein-Barr virus negative diffuse large B-cell lymphoma, it tends to have more extranodal involvement, does not respond to chemoimmunotherapy well, and has worse prognosis. We have encountered a patient with Epstein-Barr virus positive diffuse large B-cell lymphoma of thyroid gland in 75-year-old female presenting with aggravating dyspnea and neck pain.

IKS03, a Novel CD19-Targeted Antibody Drug Conjugate, Induces Target Dependent In Vivo Cell Killing of B-Cell Lymphoma Xenografts By DNA Crosslinking

CD19 is widely expressed in B-cell non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). IKS03 is a CD19-targeting antibody drug conjugate (ADC) with a novel linker payload design for tumor-selective payload release. Site-specific conjugation using farnesyltransferase-catalysed ConjuALL technology to a DNA crosslinking agent yields a homogenous ADC with drug-to-antibody ratio (DAR) of 2. To minimize systemic release of the highly potent payload in human plasma, IKS03 incorporates a linker specifically cleavable by the lysosomal enzyme beta-glucuronidase. In addition, the payload is a pro-drug with a protecting moiety cleavable by the same enzyme. Therefore, following CD19-dependent binding and uptake, IKS03 requires intracellular lysosomal processing in the target cell to both release and fully activate the free pyrrolobenzodiazepine (PBD) dimer payload which induces DNA crosslinking, blocks DNA replication and ultimately leads to tumor selective cell death. In vivo efficacy was evaluated in CD19-expressing preclinical human xenograft models representing different subtypes of B-NHL. IKS03 was highly active against Farage and OCI-LY10 DLBCL xenografts as well as Granta-519 MCL xenografts in SCID mice with durable tumor regressions observed following treatment with a single dose of 0.1 to 0.3 mg/kg. Likewise, in a Ramos lymphoma model a single IKS03 dose of 0.3 mg/kg significantly inhibited tumor growth. IKS03 demonstrated greater in vivo efficacy than the clinical benchmark ADCs polatuzumab vedotin and loncastuximab tesirine approved for the treatment of patients with B-cell non-Hodgkin lymphomas. PBD cytotoxic agents have been described to induce DNA crosslinking leading to DNA damage. To demonstrate that IKS03 in vivo activity is the result of targeted payload release, Ramos xenografts were established in immunodeficient mice and treated with up to 1 mg/kg of IKS03 in comparison with a non-targeted ADC utilizing the same linker payload format. Tumors were excised at 1 day and 3 days post-treatment and assessed for the presence of phospho-H2AX positive foci, a marker of DNA damage, by immunohistochemistry. IKS03 treatment increased both frequency and staining intensity of nuclear phospho-H2AX foci in Ramos xenografts in a dose- and time-dependent manner. In contrast, the non-targeted control ADC did not result in any changes as compared to a vehicle control. This confirms the specific induction of DNA damage in CD19 positive lymphomas as a pharmacodynamic response to IKS03 treatment in vivo. In conclusion, IKS03 is highly effective in an array of preclinical MCL and DLBCL xenograft models at doses that are well tolerated. In vivo, IKS03 treatment increased the level of phospho-H2AX indicative of irreversible DNA damage in a target-dependent manner. This is consistent with the proposed mechanism of action of CD19-mediated delivery of a PBD payload specifically to B-cell tumors. Clinical investigation in patients with advanced B-Cell Non-Hodgkin Lymphomas is being initiated (NCT05365659).

High Grade B-Cell Lymphoma with 11q Aberration Is Not a Rare Event in HIV-Associated Lymphoma

High grade B-cell lymphoma with 11q aberration/diffuse large cell lymphoma with 11q aberration (HGBL-11q; previously classified as Burkitt-like lymphoma with 11q aberration, a provisional category in WHO 4-revised) is a relatively new entity recognized by both the WHO-5 and International Consensus Classification (ICC). These lesions show high grade morphology which is often, but not always, similar to Burkitt lymphoma (BL), and a genetic composition that is similar to that of germinal center (GC) derived diffuse large cell lymphoma (DLBCL). While these lymphomas have been described in immunocompetent patients, where they occur usually in children/adolescents and adults under 60 years, they have been only been rarely described in HIV positive patients. In this study we examined the incidence of the 11q aberration in HIV positive lymphomas. Four tissue microarrays (TMA) containing 144 HIV-associated lymphomas (HIV-NHLs; 57 pre-ART; 16 females; median age 44 years) were examined for the 11q aberration by FISH using the ZytoLight SPEC 11q gain/loss Triple Color Probe (ZytoVision GmbH, Fischai1, Germany). The cases were classified morphologically, evaluated for cell of origin (Hans' criteria; immunohistochemistry for CD10, BCL6, MUM1), the presence of Kaposi sarcoma herpesvirus (KSHV; immunohistochemistry for LANA) and the Epstein Barr virus (EBV; in situ hybridization; EBER probe). Clinical data, when available, was obtained from the EMR. Of the 144 cases, 123 (85%) were evaluable by FISH, including 76 DLBCLs, 10 BL, 14 primary effusion lymphoma (PEL)/EC-PEL, 7 plasmablastic lymphomas, 1 marginal zone lymphomas and 15 polymorphic lymphoproliferative lesions. Four abnormal patterns were seen (Table 1) in 39 cases (32%): polysomy (≥ 3 copies of chromosome 11), 11q23q24 amplification (≥10 copies), variant or atypical 11q aberration (11q24 loss only) and classic or typical 11q aberration (11q23 gain and 11q24 loss). Although survival data was available in only a proportion of HIV+ patients with HGBL-11q, these patients showed in general better survival than patients with other chromosome 11 abnormalities (Table 1) and appear to trend to better survivals compared to HIV+ lymphoma patients without the 11q aberration (alive: 11-202 mo; median 73 mo; died 1 - 45 mo; median 6 mo). Our results demonstrate that chromosome 11 abnormalities are not an uncommon finding in HIV positive lymphoproliferative lesions. Furthermore, although previously only rarely described in HIV+ individuals, HIV-associated lymphomas with the classic or variant 11q aberration is not a rare event. As in immunocompetent patients, the HIV-associated high grade B cell lymphomas with 11q aberration are usually of germinal center origin and EBV negative and in at least some patients are associated with a relatively good prognosis. Thus, these findings indicate that HIV-associated high grade B cell lymphomas with 11q aberration exhibit similar biologic features as those arising in immunocompetent individuals.

Discovery of a Novel, First-in-Class Bfl-1 BH3 Mimetic with Pro-Apoptotic Activity

Background: Intrinsic apoptosis is regulated by the B Cell lymphoma 2 (BCL-2) protein family. Anti-apoptotic family members, such as BCL-2, MCL-1 and BFL-1, sequester their pro-apoptotic counterparts through a highly conserved BH3 binding groove. Disruption of this balance leads to mitochondrial pore formation and subsequent cell death. To evade apoptosis, tumors often upregulate the expression of one or more anti-apoptotic family members and as such they have become attractive targets for anti-cancer drug development. BFL-1 (‘Bcl-2 related gene expressed in fetal liver’, gene name BCL2A1) is a lesser-known anti-apoptotic family member, physiologically mainly expressed in the hematopoietic system. BCL2A1 overexpression has been reported in many types of B cell lymphoma. Diffuse Large B Cell Lymphoma (DLBCL) patient sample analysis showed that BCL2A1 expression levels are second only to MCL1 within the anti-apoptotic family. Expression of BFL-1 was shown to be upregulated in MYC+/BCL2+ double hit lymphoma cell lines treated with the BCL-2 inhibitor, Venetoclax, in vivo. Interestingly, BFL-1 positive lymphomas are less sensitive to inhibition of BCL-2 and MCL-1. Hence, targeting BFL-1 is a rational and attractive strategy in DLBCL to improve clinical outcome. Methods: Using hit identification screens followed by iterative structure-activity relationship (SAR) analyses and structure-based design, compound A, a first-in-class, selective BFL-1 BH3 mimetic, was identified. Compound A was evaluated using biochemical, cellular in vitro and in vivo tumor efficacy models. Results: Compound A is a highly potent and selective compound in biochemical assays. In BFL-1 sensitive lymphoma cell lines characterized by high BFL-1 protein expression, compound A was shown to displace BAK and BIM from BFL-1, leading to downstream cleavage of caspase 3 and cell death. Interestingly, these cellular models were resistant to Venetoclax. Compound A exhibited tumor growth inhibition in an engineered BFL-1 overexpressing, MCL-1 KO human multiple myeloma xenograft model. However, in the high BFL-1 expressing SU-DHL-2 DLBCL human xenograft model, compound A did not induce significant PD (cleaved caspase 3) and efficacy in vivo. Conclusion: First-in-class selective BFL-1 BH3 mimetics are shown to specifically inhibit cell growth of lymphoma cell lines in vitro and can induce efficacy in vivo in a BFL-1 overexpressing model. Further studies may be useful to determine whether compound A elicits anti-tumor efficacy in lymphoma alone or in combination with other anti-apoptotic agents.

From Tachycardia to Lymphoma: A Case Report of CD30 Positive (ALK) T-Cell Lymphoma Initially Presenting with Cardiac Envolvement

Anaplastic Large Cell Lymphoma (ALCL), Anaplastic Lymphoma Kinase-Positive (ALK+), is a rare subtype of large cell lymphoma. Cardiac involvement as the initial presentation leading to diagnosis is extremely rare. We present a young patient with atrial tachycardia as the presenting manifastation of ALCL.

Tumor-specific targeting of polymer drug delivery systems with recombinant proteins bound via tris(nitrilotriacetic acid)

Antibody-mediated targeting is an efficient strategy to enhance the specificity and selectivity of polymer nanomedicines towards the target site, typically a tumor. However, direct covalent coupling of an antibody with a polymer usually results in a partial damage of the antibody binding site accompanied with a compromised biological activity. Here, an original solution based on well-defined non-covalent interactions between tris-nitrilotriacetic acid (trisNTA) and hexahistidine (His-tag) groups, purposefully introduced to the structure of each macromolecule, is described. Specifically, trisNTA groups were attached along the chains of a hydrophilic statistical copolymer based on N-(2-hydroxypropyl)methacrylamide (HPMA), and at the end or along the chains of thermo-responsive di-block copolymers based on N-isopropylmethacrylamide (NIPMAM) and HPMA; His-tag was incorporated to the structure of a recombinant single chain fragment of an anti-GD2 monoclonal antibody (scFv-GD2). Static and dynamic light scattering analyses confirmed that mixing of polymer with scFv-GD2 led to the formation of polymer/scFv-GD2 complexes; those prepared from thermo-responsive polymers formed stable micelles at 37 °C. Flow cytometry and fluorescence microscopy clearly demonstrated antigen-specific binding of the prepared complexes to GD2 positive murine T-cell lymphoma cells EL-4 and human neuroblastoma cells UKF-NB3, while no interaction with GD2 negative murine fibroblast cells NIH-3T3 was observed. These non-covalent polymer protein complexes represent a new generation of highly specific actively targeted polymer therapeutics or diagnostics.

Severe lympho-depletion, abrogated thymopoiesis and systemic EBV positive T-cell lymphoma of childhood, a case

Epstein-Barr virus (EBV) associated T-cell and NK-cell lymphoproliferative diseases are lethal and extremely rare in Caucasians. We expand on the clinical, immunological and histogenetic characteristics associated with this second European case (19 years old, previously healthy, Caucasian boy) of systemic EBV positive T-cell lymphoma of childhood. We report, as novel findings, severe lympho-depletion and abrogation of thymopoiesis secondary to severe EBV activation and excessive immune activation. Similar to the first European case, we also detected a somatic missense variant in the proto-oncogene FYN. In the first European patient however, the FYN variant allele frequency (VAF) was 10% and the patient only experienced moderate leukopenia, whereas in our case, the VAF was 48% and the patient experienced severe leukopenia and lymphopenia. This could suggest a pathogenic role of these FYN variants in driving excessive T cell activation. If confirmed, FYN might become target in future treatments of this fatal disorder.

Surgical removal of an unusual huge solitary fibrous tumor in the mediastinum: a case report

BackgroundIntrathoracic Solitary Fibrous Tumors (SFT) mainly arise from the pleura; however, these tumors may also originate from the mediastinum. We present a rare case of posterior SFT extending to several mediastinal sites and with an unusual large size, successfully treated with surgical resection.Case presentationA 66-year-old female presented with an initial manifestation of ambiguous pain in the chest and dysphagia and later developed pitting edema in both lower extremities and cachexia five months before admission. Chest imaging confirmed a mediastinal mass (17 × 15 × 8 cm) which was surgically removed. Immunohistochemistry confirmed the diagnosis of a solitary fibrous tumor with positive B-cell lymphoma 2, STAT6, and CD99, negative S100 and smooth muscle actin, and low levels of Ki67 (5–7%). The patient’s follow-up course was unremarkable.ConclusionMediastinal SFTs may grow extremely huge, with the potential to invade multiple adjacent sites. Surgical removal of the tumor remains the mainstay of treatment in these cases.

A case of Epstein-Barr virus-associated primary vitreoretinal lymphoma in an immunosuppressed patient.

To describe a rare case of Epstein-Barr virus (EBV)-positive primary vitreoretinal lymphoma (PVRL) in an immunosuppressed patient. Observational case report. A 64-year-old man under immunosuppressive therapy for rheumatic arthritis was referred for 2-month of blurred vision and decreased visual acuity in the right eye. Only mutton-fat keratic precipitates and mild vitreous opacity were found in the right eye without (sub-)retinal or sub-retinal pigment epithelial lesions. Vitreous biopsy and systemic workup suggested the diagnosis of PVRL of diffuse large B cell lymphoma (DLBCL) subform. Neoplastic cells stained positive for EBV antigens, EBV-encoded small RNA and Epstein-Barr nuclear antigen 2, consistent with EBV-positive DLBCL. Intravitreal methotrexate was effective in improving ocular symptoms. Our case provided evidence on the association of EBV infection with PVRL.

Philadelphia Chromosome Positive and Philadelphia-Like Acute Lymphoblastic Leukemia in Children and Adolescents: Current Management, Controversies and Emerging Concepts.

Philadelphia chromosome positive (Ph+) acute lymphoblastic lymphoma (ALL) is an uncommon subtype of ALL in children, seen in 2-5% cases. Diagnostic evaluation includes conventional karyotyping and detection of BCR-ABL1 translocation by fluorescence in-situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR). For children, the frontline management includes combination of intensive chemotherapy along with imatinib (300-340mg/m2/d) or dasatinib (60-80mg/m2/d). Imatinib/dasatinib should be introduced in induction as soon as results for BCR-ABL are available. Minimal residual disease (MRD) monitoring is essential; multi-parametric flowcytometry and immunoglobulin/T-cell receptor rearrangement PCR are the preferred methods. Intrathecal therapy with at least 12 doses of methotrexate is adequate for central nervous system (CNS) prophylaxis, but cranial radiation is necessary for CNS3 involvement. Allogeneic hematopoietic stem cell transplantation (HSCT) in first remission may be considered in high-risk cases (persistent MRD positivity/induction failure). Maintenance therapy with tyrosine kinase inhibitors (TKI) in children is debatable, with potential concerns for long term adverse effects. At relapse, the choice of TKI is guided by the presence of BCR-ABL tyrosine kinase domain resistance mutations, although the frequency of resistance mutations in children are lower. Allogeneic HSCT is essential for consolidation in second remission, if not done.Ph-like ALL is a newly recognized molecular entity, with gene expression profile similar to Ph+ALL and poor survival outcomes. In resource-constrained settings, a stepwise cost-effective diagnostic evaluation should be considered among high-risk patients without recurrent genetic abnormalities. Current treatment strategies remain similar to Ph-negative ALL. Enrolment in clinical trials is encouraged for such children to evaluate potential targeted agents in this subtype.

Gastrointestinal ALK-positive anaplastic large cell lymphoma: a clinicopathological analysis of five cases

Objective: To investigate the clinicpathological characteristics of ALK-positive anaplastic large cell lymphoma (ALCL) of the gastrointestinal tract, and to discuss its diagnosis and differential diagnosis. Methods: Five cases of gastrointestinal ALK-positive ALCL diagnosed and treated in Xijing Hospital of the Fourth Military Medical University, between 2011 and 2019 were collected. There were three male and two female patients, aged 5-42 years (mean 25 years). These patients clinically presented with fever and night sweats, weight loss, abdominal pain, abdominal mass, ulcers, bleeding, or intestinal obstruction, and underwent surgical resection of the tumors or endoscopic biopsy. The clinical manifestations, auxiliary examinations, histopathological characteristics, immunophenotypes and genetic alterations were analyzed. Results: In this cohort, one case was common type, two cases were monomorphic variant of common type, and two cases were small cell variant. The tumor cells in all cases expressed ALK, CD30, and one or more T lymphocyte markers, while all the markers of B lymphocyte and plasmacyte were negative. Clonality analysis showed that two cases had clonal T cell receptor (TCR) and immunoglobulin (Ig) gene rearrangement, one case had no clonal TCR but Ig gene rearrangement, and one case had no clonal TCR and Ig gene rearrangements. During the 4 to 67 months' follow-up, two patients died of the disease, two were alive with free of disease and one had a relapse. Conclusions: ALK-positive ALCL of the gastrointestinal tract is extremely rare, and has poor prognosis. Lymphoma originating from this site with CD30 and ALK-positive phenotypes may be considered to be ALCL; however differentiation from other tumors that had anaplastic features, expressed CD30 and or ALK, in particular, ALK positive large B-cell lymphoma is necessary.

Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas.

Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV+) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV+PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV+PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV-PCNSL. Instead, EBV+PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+PCNSL. In addition to novel insights into the pathobiology of EBV+PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.

Dual epigenetic therapy in TET2 gene positive extranodal peripheral T-cell lymphoma with follicular helper T-cell (TFH) phenotype: a case report and literature review

Dual epigenetic therapy in TET2 gene positive extranodal peripheral T-cell lymphoma with follicular helper T-cell (TFH) phenotype: a case report and literature review

IGL-CCND1 positive mantle cell lymphoma: a case report and literature review

IGL-CCND1 positive mantle cell lymphoma: a case report and literature review

Anaplastic Lymphoma Kinase Positive Large B-Cell Lymphoma Mimicking as Plasma Cell Neoplasm: A Rare Case Report

Anaplastic lymphoma kinase positive (ALK+ve) large B-cell lymphoma (LBCL) is a rare, aggressive subtype of diffuse LBCL with unique morphological characteristics and unusual immunophenotypic features that have substantial overlap with other hematologic and nonhematologic neoplasms. Here, we present a 48-year-old male who presented with progressive swelling on both sides of the neck and left eye followed by protruding mass in the left nose over a span of 6 months. Based on the biopsy findings of the left nasal mass, a plasma cell neoplasm was initially diagnosed; later on the diagnosis was modified as ALK + ve LBCL based on the aggressive clinical course and biopsy findings of cervical lymph node. The patient was started on chemotherapy and is tolerating well.

Translational development of BAFF-R-specific chimeric antigen receptor T-cell therapy targeting B-cell lymphoid malignancies.

e19501 Background: Relapsed and/or refractory (R/R) disease is observed in patients who receive CD19 targeting chimeric antigen receptor (CAR)-T cells to treat B-cell lymphoid leukemias and lymphomas. We generated a novel CAR, MC10029 that targets B-cell activating factor receptor (BAFF-R) to address this unmet medical need. Methods: We engineered a second-generation BAFF-R CAR (MC10029 CAR). The construct includes the single chain variable fragment (scFv) of our newly developed BAFF-R antibody with CD28 costimulatory and CD3ζ signaling domains. We confirmed MC10029 CAR-T cell antigen-specific activation with in vitro degranulation assays and a direct cytolytic assay. We used BAFF-R positive leukemia and lymphoma cell lines in both in vitro and in vivo models to further characterize MC10029 CAR-T cells, and finally, we enriched tumor primary cells from chronic lymphocytic leukemia (CLL) patients as a target for MC10029 CAR-T cells. In preparation for our Phase I clinical trial, we have manufactured three batches of CAR-T cells using a MC10029-encoding lentiviral vector produced under GMP conditions. The production batches of MC10029 CAR-T cells were evaluated for product quality with Viability, Identity and Potency as well as Safety from adventitious viral agents. Antigen specific cytotoxicity of the MC10029 CAR-T cells was confirmed using our standard degranulation assay. Results: MC10029 CAR-T cells elicited in vitro antigen-specific cytotoxicity against Nalm-6 cells, Z138 cells, MEC-1 cells, and a CD19 knock out Nalm-6 model designed to mimic CD19-negative R/R disease. We demonstrated in vivo antitumor effects of MC10029 CAR-T cells in NSG mice challenged with these same cell lines. We showed cytotoxicity of MC10029 CAR-T cells against CLL patients’ tumors. We also showed our quality control results to highlight our clinical trial trajectory. Conclusions: Novel MC10029 CAR-T cells showed broad utility against BAFF-R positive B-cell lymphoid malignancies in a series of in vitro, in vivo, and ex vivo models. With these robust data, we have moved forward to generate clinical grade MC10029 CAR-T cells using cGMP manufacturing and quality protocols in preparation of a MC10029 CAR-T cell Phase I clinical trial.

A transposable element atlas of aggressive B‐cell non‐Hodgkin lymphomas defines novel classifications of Burkitt lymphoma independent of EBV status

Introduction: Clinical and pathological heterogeneity in aggressive B-cell non-Hodgkin lymphomas may be driven by several mechanisms of oncogenesis, such as translocations involving the immunoglobulin locus and proto-oncogenes, the ‘cell-of-origin’ from the germinal center (GC), and viral associations. Previous classifications of B-cell lymphomas have been defined by one or more of these characteristics and transforming events. However, transposable elements (TEs), which make up roughly half of the human genome and have key regulatory functions, have been previously overlooked in both the healthy GC and in B-cell lymphomas. We hypothesized that unique TE signatures, which may in part be driven by human endogenous retroviruses (HERVs), would allow a novel categorization of B-cell lymphomas. Here we present a comprehensive, locus-specific atlas of TE expression in healthy GC B cells, diffuse large B-cell lymphoma (DLBCL), Epstein-Barr Virus (EBV)-positive and negative Burkitt lymphoma (BL), and follicular lymphoma (FL). Methods: We obtained RNA-seq data from 529 DLBCLs belonging to the TCGA and NCICCR cohorts, 113 sporadic and endemic BL, and 12 FL from the CGCI cohort for gene and locus-specific TE quantification. RNA-seq data from sorted cells from the healthy GC were obtained from two recent studies (Holmes et al., 2020; Agirre et al., 2019). TEs were quantified with Telescope, which addresses the computational challenges of repetitive and interspersed TE reads, and low read counts using an expectation-maximization algorithm. We used STAR for indexing and alignment, HTSeq for quantifying EBV viral reads in endemic BL samples, DESeq2 to identify differentially expressed TEs, and LRT, Boruta, and Lasso for feature selection. Results: TE-driven clustering of healthy B cells showed that HERVs could independently distinguish stages of B cell differentiation and specific GC subsets, with plasmablasts and bone marrow plasma cells having the highest number of differentially expressed HERVs. We found HERV loci of interest upstream of POU5F1B and MYC that can differentiate plasmablasts from other GC cells. Furthermore, we describe a map of locus-specific TE expression in DLBCL, BL, and FL. Strikingly, we find that BL can be subdivided into three HERV-driven clusters, which are not obtained with gene-only clustering, and identify 4 HERV loci sufficient to distinguish between clusters. Clusters are independent of EBV status, clinical variant, location of MYC translocation, and display a high number of differentially expressed LINE elements, lncRNAs, and snoRNAs. Conclusions: Here, we report an atlas of TE expression in BL, DLBCL, and FL, and provide evidence for disease-specific changes in TE expression in B-cell lymphomas. TEs that are selectively expressed in lymphoma subtypes provide opportunities for novel subclassification that may have biological and pathological relevance. The research was funded by: The work was supported in part by US National Institutes of Health (NIH) grant CA260691 (DFN), and UM1AI164559 (DFN). MLB is supported in part by the Department of Medicine, Fund for the Future program at Weill Cornell Medicine sponsored by the Elsa Miller Foundation. J.L.M. was supported in part by a Medical Scientist Training Program grant to the Weill Cornell–Rockefeller–Sloan Kettering Tri-Institutional MD-PhD Program (T32GM007739). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Bioinformatics, Computational and Systems Biology, Pathology and Classification of Lymphomas No conflicts of interests pertinent to the abstract.

Epstein Barr Virus Positive Hodgkin's Lymphoma in a Patient with NEMO Deficiency

IntroductionHypomorphic mutations in the NF-kappaB essential modulator (NEMO) can manifest in diverse ways, but are best characterized by early susceptibility to viral, pyogenic and mycobacterial infections, ectodermal dysplasia and absent pneumococcal responses. We describe a case of EBV+ Hodgkin's lymphoma in a 9-year-old patient with NEMO on antimicrobial prophylaxis and immunoglobulin replacement therapy (IgRT). Case reportOur patient was diagnosed with NEMO deficiency at 2 years with initial presentation of recurrent pneumonia, recurrent skin abscesses and severe eczema herpeticum. His disease was moderately controlled with IgRT, and prophylaxis with trimethoprim/sulfamethoxazole, azithromycin and acylovir prophylaxis, with primary complications of continued recurrent pneumonia and finger clubbing. At 9 years of age however, he developed acute back pain and weakness, along with night sweats. MRI revealed thoracic spinal cord compression at T5 secondary to a possible neoplastic soft tissue mass. A laminectomy revealed Epstein Barr virus (EBV) positive Hodgkin lymphoma, stage 4 high risk due to PET positivity with uptake at large cervical chain nodal conglomerates bilaterally, mediastinal mass, thoracic paraspinal mass, periportal lymph nodes, splenic, and right medial femoral neck. He also had low level EBV viremia (EBV viral load 7,515 IU/mL). He was treated according to AHOD1331 with ABVE-PC (doxorubicin/bleomycin/vincristine/etoposide/prednisone), and also received rituximab and valganciclovir for treatment of EBV. He is now in remission after 4 months of treatment, and continues on IgRT, pneumocystis jiroveci pneumonia, mycobacterium avium complex, and herpes simplex virus prophylaxis. ConclusionPatients with certain inborn errors of immunity have a higher incidence of malignancy due to impaired immune function. Despite their viral susceptibility, EBV-induced lymphomas are not common in NEMO deficiency. NEMO patients may need further enhanced screening for development of malignancy, including regular surveillance for chronic, cancer-causing infections such as EBV and HPV.

A nuclear NKRF interacting long noncoding RNA controls EBV eradication and suppresses tumor progression in natural killer/T-cell lymphoma

Long intergenic noncoding RNAs (lincRNAs) are differentially expressed in EBV-infected cells and play an essential role in tumor progression. Molecular pathogenesis of lincRNAs in EBV-driven natural killer T cell lymphoma (NKTCL) remains unclear. Here we investigated the ncRNA profile using high-throughput RNA sequencing data of 439 lymphoma samples and screened out LINC00486, whose downregulation was further validated by quantitative real-time polymerase chain reaction in EBV-encoded RNA (EBER)-positive lymphoma, particularly NKTCL. Both in vitro and in vivo studies revealed the tumor suppressive function of LINC00486 through inhibiting tumor cell growth and inducing G0/G1 cell cycle arrest. As mechanism of action, LINC00486 specifically interacted with NKRF to abrogate its binding with phosphorylated p65, activated NF-κB/TNF-α signaling and subsequently enhanced EBV eradication. Solute carrier family 1 member 1 (SLC1A1), upregulated and mediated the glutamine-addiction and tumor progression in NKTCL, was negatively correlated with the expression of NKRF. NKRF specifically bound to the promoter and transcriptionally downregulated the expression of SLC1A1, as evidenced by Chromatin Immunoprecipitation (ChIP) and luciferase assay. Collectively, LINC00486 functioned as a tumor suppressor and counteracted EBV infection in NKTCL. Our study improved the knowledge of EBV-driven oncogenesis in NKTCL and provided the clinical rationale of EBV eradication in anti-cancer treatment.

A rare case of primary lymphoma of the ciliary body – A case report

A 73-year-old lady presented with complicated cataract, white tumor hypopyon, and an elevated, nonpigmented mass at the root of iris. Magnetic resonance imaging (MRI) revealed ciliary body involvement suspicious of atypical melanoma. Patient underwent enucleation. Histopathology with immunohistochemistry (IHC) markers clinched the diagnosis of diffuse large B-cell lymphoma (DLBCL) of ciliary body, with positive lymphoma markers CD20, CD3, BCL2, and PAX5 and negative melanoma markers HMB45 and S100. Primary lymphoma of ciliary body, especially the DLBCL type, is rare. Our report shows that primary lymphoma of ciliary body may be considered as a differential in cases with atypical features. Histopathology and immunohistochemistry are valuable tools in diagnosing challenging cases.