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1.
Cell ; 186(18): 3882-3902.e24, 2023 08 31.
Article in English | MEDLINE | ID: mdl-37597510

ABSTRACT

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.


Subject(s)
COVID-19 , Epigenetic Memory , Post-Acute COVID-19 Syndrome , Animals , Humans , Mice , Cell Differentiation , COVID-19/immunology , Disease Models, Animal , Hematopoietic Stem Cells , Inflammation/genetics , Trained Immunity , Monocytes/immunology , Post-Acute COVID-19 Syndrome/genetics , Post-Acute COVID-19 Syndrome/immunology , Post-Acute COVID-19 Syndrome/pathology
2.
Cell ; 182(2): 297-316.e27, 2020 07 23.
Article in English | MEDLINE | ID: mdl-32619424

ABSTRACT

The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.


Subject(s)
Immunologic Memory/physiology , Lymphoma, Large B-Cell, Diffuse/pathology , Nuclear Proteins/genetics , Precursor Cells, B-Lymphoid/immunology , Receptors, Cytoplasmic and Nuclear/genetics , Repressor Proteins/genetics , Animals , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Chromatin/chemistry , Chromatin/metabolism , Germinal Center/cytology , Germinal Center/immunology , Germinal Center/metabolism , Histone Deacetylases/metabolism , Humans , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutagenesis, Site-Directed , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Nuclear Receptor Co-Repressor 2/chemistry , Nuclear Receptor Co-Repressor 2/metabolism , Precursor Cells, B-Lymphoid/cytology , Precursor Cells, B-Lymphoid/metabolism , Protein Binding , Proto-Oncogene Proteins c-bcl-6/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Cytoplasmic and Nuclear/metabolism , Repressor Proteins/chemistry , Repressor Proteins/metabolism , Transcription, Genetic
3.
Cell ; 171(2): 481-494.e15, 2017 Oct 05.
Article in English | MEDLINE | ID: mdl-28985567

ABSTRACT

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.


Subject(s)
CRISPR-Cas Systems , Gene Expression Profiling , Lymphoma, Large B-Cell, Diffuse/genetics , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cells, Cultured , Exome , Female , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Male , Rituximab/administration & dosage
4.
Blood ; 141(8): 904-916, 2023 02 23.
Article in English | MEDLINE | ID: mdl-36201743

ABSTRACT

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.


Subject(s)
Burkitt Lymphoma , Epstein-Barr Virus Infections , Lymphoma, Large B-Cell, Diffuse , Child , Humans , Adult , Burkitt Lymphoma/pathology , Herpesvirus 4, Human , Lymphoma, Large B-Cell, Diffuse/pathology , Mutation
5.
Mod Pathol ; 37(4): 100441, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38309432

ABSTRACT

We review B-cell neoplasms in the 5th edition of the World Health Organization classification of hematolymphoid tumors (WHO-HEM5). The revised classification is based on a multidisciplinary approach including input from pathologists, clinicians, and other experts. The WHO-HEM5 follows a hierarchical structure allowing the use of family (class)-level definitions when defining diagnostic criteria are partially met or a complete investigational workup is not possible. Disease types and subtypes have expanded compared with the WHO revised 4th edition (WHO-HEM4R), mainly because of the expansion in genomic knowledge of these diseases. In this review, we focus on highlighting changes and updates in the classification of B-cell lymphomas, providing a comparison with WHO-HEM4R, and offering guidance on how the new classification can be applied to the diagnosis of B-cell lymphomas in routine practice.


Subject(s)
Hematologic Neoplasms , Lymphoma, B-Cell , Humans , Lymphoma, B-Cell/pathology , World Health Organization , Pathologists , Hematologic Neoplasms/pathology
6.
Blood ; 139(7): 1013-1025, 2022 02 17.
Article in English | MEDLINE | ID: mdl-34479367

ABSTRACT

Kaposi sarcoma (KS) herpesvirus (KSHV), also known as human herpesvirus 8, is the causal agent of KS but is also pathogenetically related to several lymphoproliferative disorders, including primary effusion lymphoma (PEL)/extracavitary (EC) PEL, KSHV-associated multicentric Castleman disease (MCD), KSHV+ diffuse large B-cell lymphoma, and germinotropic lymphoproliferative disorder. These different KSHV-associated diseases may co-occur and may have overlapping features. KSHV, similar to Epstein-Barr virus (EBV), is a lymphotropic gammaherpesvirus that is preferentially present in abnormal lymphoid proliferations occurring in immunecompromised individuals. Notably, both KSHV and EBV can infect and transform the same B cell, which is frequently seen in KSHV+ EBV+ PEL/EC-PEL. The mechanisms by which KSHV leads to lymphoproliferative disorders is thought to be related to the expression of a few transforming viral genes that can affect cellular proliferation and survival. There are critical differences between KSHV-MCD and PEL/EC-PEL, the 2 most common KSHV-associated lymphoid proliferations, including viral associations, patterns of viral gene expression, and cellular differentiation stage reflected by the phenotype and genotype of the infected abnormal B cells. Advances in treatment have improved outcomes, but mortality rates remain high. Our deepening understanding of KSHV biology, clinical features of KSHV-associated diseases, and newer clinical interventions should lead to improved and increasingly targeted therapeutic interventions.


Subject(s)
Epstein-Barr Virus Infections/complications , Hematologic Diseases/pathology , Herpesvirus 4, Human/isolation & purification , Herpesvirus 8, Human/isolation & purification , Lymphoproliferative Disorders/pathology , Sarcoma, Kaposi/complications , Epstein-Barr Virus Infections/virology , Hematologic Diseases/epidemiology , Hematologic Diseases/virology , Humans , Lymphoproliferative Disorders/epidemiology , Lymphoproliferative Disorders/virology , Sarcoma, Kaposi/virology
8.
Blood ; 137(24): 3378-3389, 2021 06 17.
Article in English | MEDLINE | ID: mdl-33786583

ABSTRACT

A small subset of cases of chronic lymphocytic leukemia undergoes transformation to diffuse large B-cell lymphoma, Richter syndrome (RS), which is associated with a poor prognosis. Conventional chemotherapy results in limited responses, underlining the need for novel therapeutic strategies. Here, we investigate the ex vivo and in vivo efficacy of the dual phosphatidylinositol 3-kinase-δ/γ (PI3K-δ/γ) inhibitor duvelisib (Duv) and the Bcl-2 inhibitor venetoclax (Ven) using 4 different RS patient-derived xenograft (PDX) models. Ex vivo exposure of RS cells to Duv, Ven, or their combination results in variable apoptotic responses, in line with the expression levels of target proteins. Although RS1316, IP867/17, and RS9737 cells express PI3K-δ, PI3K-γ, and Bcl-2 and respond to the drugs, RS1050 cells, expressing very low levels of PI3K-γ and lacking Bcl-2, are fully resistant. Moreover, the combination of these drugs is more effective than each agent alone. When tested in vivo, RS1316 and IP867/17 show the best tumor growth inhibition responses, with the Duv/Ven combination leading to complete remission at the end of treatment. The synergistic effect of Duv and Ven relies on the crosstalk between PI3K and apoptotic pathways occurring at the GSK3ß level. Indeed, inhibition of PI3K signaling by Duv results in GSK3ß activation, leading to ubiquitination and subsequent degradation of both c-Myc and Mcl-1, making RS cells more sensitive to Bcl-2 inhibition by Ven. This work provides, for the first time, a proof of concept of the efficacy of dual targeting of PI3K-δ/γ and Bcl-2 in RS and providing an opening for a Duv/Ven combination for these patients. Clinical studies in aggressive lymphomas, including RS, are under way. This trial was registered at www.clinicaltrials.gov as #NCT03892044.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class Ib Phosphatidylinositol 3-Kinase , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Class I Phosphatidylinositol 3-Kinases/metabolism , Female , Humans , Isoquinolines/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Male , Mice , Proto-Oncogene Proteins c-bcl-2/metabolism , Purines/pharmacology , Sulfonamides/pharmacology , Xenograft Model Antitumor Assays
9.
Blood ; 137(24): 3365-3377, 2021 06 17.
Article in English | MEDLINE | ID: mdl-33512452

ABSTRACT

Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL), typically to an aggressive lymphoma. Treatment options for RS are limited and the disease is often fatal. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed on CLL cells and other cancers but not on healthy adult tissues, making it an attractive, tumor-specific therapeutic target. VLS-101 is being developed as an antibody-drug conjugate (ADC) for therapy of ROR1-expressing (ROR1+) cancers. VLS-101 comprises UC-961 (a humanized immunoglobulin G1 monoclonal antibody that binds an extracellular epitope of human ROR1), a maleimidocaproyl-valine-citrulline-para-aminobenzoate linker, and the antimicrotubule cytotoxin monomethyl auristatin E (MMAE). VLS-101 binding to ROR1 results in rapid cellular internalization and delivery of MMAE to induce tumor cell death. We studied 4 RS patient-derived xenografts (RS-PDXs) with varying levels of ROR1 expression (11%, 32%, 85%, and 99% of cells). VLS-101 showed no efficacy in the lowest-expressing RS-PDX but induced complete remissions in those with higher levels of ROR1 expression. Responses were maintained during the posttherapy period, particularly after higher VLS-101 doses. In systemic ROR1+ RS-PDXs, VLS-101 dramatically decreased tumor burden in all RS-colonized tissues and significantly prolonged survival. Animals showed no adverse effects or weight loss. Our results confirm ROR1 as a target in RS and demonstrate the therapeutic potential of using an ADC directed toward ROR1 for the treatment of hematological cancers. A phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with RS and other hematological malignancies.


Subject(s)
Aminobenzoates/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Drug Delivery Systems , Immunoconjugates/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Oligopeptides/pharmacology , Receptor Tyrosine Kinase-like Orphan Receptors/antagonists & inhibitors , Aminobenzoates/chemistry , Animals , Antineoplastic Agents, Immunological/chemistry , Humans , Immunoconjugates/chemistry , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Mice , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Neoplasm Proteins/metabolism , Oligopeptides/chemistry , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Xenograft Model Antitumor Assays
10.
J Gen Intern Med ; 2023 Nov 22.
Article in English | MEDLINE | ID: mdl-37993739

ABSTRACT

BACKGROUND: Guidelines recommend high-sensitivity cardiac troponin (hs-cTn) for diagnosis of myocardial infarction. Use of hs-cTn is increasing across the U.S., but questions remain regarding clinical and operational impact. Prior studies have had methodologic limitations and yielded conflicting results. OBJECTIVE: To evaluate the impact of transitioning from conventional cardiac troponin (cTn) to hs-cTn on test and resource utilization, operational efficiency, and patient safety. DESIGN: Retrospective cohort study in two New York City hospitals during the months before and after transition from conventional cTn to hs-cTn at Hospital 1. Hospital 2 served as a control. PARTICIPANTS: Consecutive emergency department (ED) patients with at least one cTn test resulted. INTERVENTION: Multifaceted hs-cTn intervention bundle, including a 0/2-h diagnostic algorithm for non-ST-elevation myocardial infarction, an educational bundle, enhancements to the electronic medical record, and nursing interventions to facilitate timed sample collection. MAIN MEASURES: Primary outcomes included serial cTn test utilization, probability of hospital admission, ED length of stay (LOS), and among discharged patients, probability of ED revisit within 72 h resulting in hospital admission. Multivariable regression models adjusted for age, sex, temporal trends, and interhospital differences. KEY RESULTS: The intervention was associated with increased use of serial cTn testing (adjusted risk difference: 48 percentage points, 95% CI: 45-50, P < 0.001) and ED LOS (adjusted geometric mean difference: 50 min, 95% CI: 50-51, P < 0.001). There was no significant association between the intervention and probability of admission (adjusted relative risk [aRR]: 0.99, 95% CI: 0.89-1.1, P = 0.81) or probability of ED revisit within 72 h resulting in admission (aRR: 1.1, 95% CI: 0.44-2.9, P = 0.81). CONCLUSIONS: Implementation of a hs-cTn intervention bundle was associated with an improvement in serial cTn testing, a neutral effect on probability of hospital admission, and a modest increase in ED LOS.

11.
J Natl Compr Canc Netw ; 21(3): 323-330, 2023 03.
Article in English | MEDLINE | ID: mdl-36898366

ABSTRACT

Primary mediastinal B-cell lymphoma (PMBCL) is a rare but aggressive mature B-cell lymphoma that arises from thymic B cells and most commonly affects adolescents and young adults. PMBCL is now recognized by the WHO as a distinct entity from diffuse large B-cell lymphoma (DLBCL), not otherwise specified, with a unique clinical presentation and distinct morphologic features and molecular alterations. Similar to classic Hodgkin lymphoma, PMBCL tumors are characterized by alterations in the nuclear factor-κB and JAK/STAT pathways. These tumors also exhibit an immune evasion phenotype marked by upregulation of PD-L1 and loss of B2M. Historic data indicates that outcomes for pediatric patients with PMBCL are inferior compared with pediatric patients with DLBCL treated on the same protocols, and there is no current standard approach to initial treatment. Common regimens used for children with PMBCL include multiagent chemotherapy regimens designed for Burkitt lymphoma, such as Lymphomes Malins B (LMB)-based or Berlin-Frankfurt-Münster (BFM)-based chemotherapy ± rituximab. Based on initial data in adults showing excellent outcomes with the use of DA-EPOCH-R regimens, these regimens have also been adopted in pediatrics, although with mixed results. Novel agents are currently being studied in PMBCL with the goal of improving outcomes and reducing reliance on radiation and/or high-dose chemotherapy. Immune checkpoint blockade with PD-1 inhibition is of particular interest given the upregulation of PD-L1 in PMBCL and the known efficacy of these agents in the relapsed setting. Future efforts in PMBCL will also seek to determine the role of FDG-PET in evaluating response to therapy and the role of biomarkers in risk stratification.


Subject(s)
Hodgkin Disease , Lymphoma, Large B-Cell, Diffuse , Mediastinal Neoplasms , Humans , Child , B7-H1 Antigen/therapeutic use , Rituximab/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Hodgkin Disease/etiology , Mediastinal Neoplasms/drug therapy , Mediastinal Neoplasms/pathology
12.
Pathobiology ; 90(5): 356-364, 2023.
Article in English | MEDLINE | ID: mdl-36996787

ABSTRACT

INTRODUCTION: Primary effusion lymphoma (PEL) is a malignant lymphomatous effusion, which by definition is Kaposi sarcoma herpesvirus/human herpesvirus 8-positive. PEL typically occurs in HIV-infected patients but can also occur in HIV-negative individuals, including in organ transplant recipients. Tyrosine kinase inhibitors (TKIs) are currently the standard of care for patients with chronic myeloid leukemia (CML), BCR::ABL1-positive. Although TKIs are extremely effective in treating CML, they alter T-cell function by inhibiting peripheral T-cell migration and altering T-cell trafficking and have been associated with the development of pleural effusions. CASE PRESENTATION: We report a case of PEL in a young, relatively immunocompetent patient with no history of organ transplant receiving dasatinib for CML, BCR::ABL1-positive. DISCUSSION: We hypothesize that the loss of T-cell function secondary to TKI therapy (dasatinib) may have resulted in the unchecked cellular proliferation of Kaposi sarcoma herpesvirus (KSHV)-infected cells, leading to the emergence of a PEL. We recommend cytologic investigation and KSHV testing in patients being treated with dasatinib for CML who present with persistent or recurrent effusions.


Subject(s)
HIV Infections , Herpesvirus 8, Human , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Lymphoma, Primary Effusion , Sarcoma, Kaposi , Humans , Dasatinib/adverse effects , Lymphoma, Primary Effusion/diagnosis , Lymphoma, Primary Effusion/drug therapy , Lymphoma, Primary Effusion/chemically induced , Sarcoma, Kaposi/chemically induced , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/chemically induced , HIV Infections/complications , HIV Infections/drug therapy
13.
Semin Diagn Pathol ; 40(6): 401-407, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37596187

ABSTRACT

Post-transplant lymphoproliferative disorders are a well-recognized complication of solid organ and stem cell transplantation. Much data has accumulated with respect to the pathobiology and clinical behavior of these lesions in the general post-transplant population as well as in the pediatric and adult age groups. However, information as to these lesions in the adolescent and young adult populations, which bridge the pediatric and adult groups, is limited. In this review, the focus is on this unique population of PTLD patients and their proliferations.


Subject(s)
Epstein-Barr Virus Infections , Lymphoproliferative Disorders , Humans , Child , Adolescent , Young Adult , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/etiology , Epstein-Barr Virus Infections/complications
14.
J Biol Chem ; 296: 100100, 2021.
Article in English | MEDLINE | ID: mdl-33208460

ABSTRACT

Normal human cells can either synthesize cholesterol or take it up from lipoproteins to meet their metabolic requirements. In some malignant cells, de novo cholesterol synthesis genes are transcriptionally silent or mutated, meaning that cholesterol uptake from lipoproteins is required for survival. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also subject to ferroptosis, an oxygen- and iron-dependent cell death mechanism triggered by accumulation of oxidized lipids in cell membranes unless the lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), reduces these toxic lipid species. To study mechanisms linking cholesterol uptake with ferroptosis and determine the potential role of the high-density lipoprotein (HDL) receptor as a target for cholesterol depleting therapy, we treated lymphoma cell lines known to be sensitive to the reduction of cholesterol uptake with HDL-like nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand that binds to the receptor for cholesterol-rich HDLs, scavenger receptor type B1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells toward increased de novo cholesterol synthesis, which is accompanied by nearly complete reduction in expression of GPX4. As a result, oxidized membrane lipids accumulate, leading to cell death through a mechanism consistent with ferroptosis. We obtained similar results in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake-addicted lymphoma cells abolishes GPX4, resulting in cancer cell death by a mechanism consistent with ferroptosis.


Subject(s)
Cholesterol/metabolism , Ferroptosis , Lymphoma/metabolism , Animals , Cholesterol/genetics , Humans , Jurkat Cells , Lymphoma/genetics , Lymphoma/pathology , Mice , Mice, SCID , Neoplasm Proteins/metabolism , Oxidation-Reduction , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Scavenger Receptors, Class B/genetics , Scavenger Receptors, Class B/metabolism , U937 Cells
15.
Mod Pathol ; 35(3): 306-318, 2022 03.
Article in English | MEDLINE | ID: mdl-34584212

ABSTRACT

Peripheral T-cell lymphomas are a heterogeneous, and usually aggressive, group of mature T-cell neoplasms with overlapping clinical, morphologic and immunologic features. A large subset of these neoplasms remains unclassifiable with current diagnostic methods ("not otherwise specified"). Genetic profiling and other molecular tools have emerged as widely applied and transformative technologies for discerning the biology of lymphomas and other hematopoietic neoplasms. Although the application of these technologies to peripheral T-cell lymphomas has lagged behind B-cell lymphomas and other cancers, molecular profiling has provided novel prognostic and diagnostic markers as well as an opportunity to understand the biologic mechanisms involved in the pathogenesis of these neoplasms. Some biomarkers are more prevalent in specific T-cell lymphoma subsets and are being used currently in the diagnosis and/or risk stratification of patients with peripheral T-cell lymphomas. Other biomarkers, while promising, need to be validated in larger clinical studies. In this review, we present a summary of our current understanding of the molecular profiles of the major types of peripheral T-cell lymphoma. We particularly focus on the use of biomarkers, including those that can be detected by conventional immunohistochemical studies and those that contribute to the diagnosis, classification, or risk stratification of these neoplasms.


Subject(s)
Lymphoma, B-Cell , Lymphoma, T-Cell, Peripheral , Biomarkers , Humans , Lymphoma, B-Cell/genetics , Lymphoma, T-Cell, Peripheral/diagnosis , Lymphoma, T-Cell, Peripheral/genetics , Lymphoma, T-Cell, Peripheral/pathology , Prognosis
16.
Blood ; 136(11): 1284-1297, 2020 09 10.
Article in English | MEDLINE | ID: mdl-32430507

ABSTRACT

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Genes, myc , Lymphoma, AIDS-Related/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Adult , Aged , Anti-HIV Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , CD4 Lymphocyte Count , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , DNA, Viral/blood , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Etoposide/administration & dosage , Etoposide/adverse effects , Female , HIV Infections/drug therapy , HIV-1/drug effects , Herpesviridae Infections/complications , Herpesviridae Infections/virology , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/isolation & purification , Herpesvirus 8, Human/genetics , Herpesvirus 8, Human/isolation & purification , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/adverse effects , Humans , Kaplan-Meier Estimate , Lymphoma, AIDS-Related/complications , Lymphoma, AIDS-Related/genetics , Lymphoma, AIDS-Related/virology , Lymphoma, Non-Hodgkin/complications , Lymphoma, Non-Hodgkin/genetics , Lymphoma, Non-Hodgkin/virology , Male , Middle Aged , Neutropenia/chemically induced , Prednisone/administration & dosage , Prednisone/adverse effects , Progression-Free Survival , Prospective Studies , Rituximab/administration & dosage , Rituximab/adverse effects , Thrombocytopenia/chemically induced , Treatment Outcome , Vincristine/administration & dosage , Vincristine/adverse effects , Viral Load/drug effects , Vorinostat/administration & dosage , Vorinostat/adverse effects
17.
Clin Chem ; 67(9): 1249-1258, 2021 09 01.
Article in English | MEDLINE | ID: mdl-33914041

ABSTRACT

BACKGROUND: Low initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody titers dropping to undetectable levels within months after infection have raised concerns about long-term immunity. Both the antibody levels and the avidity of the antibody-antigen interaction should be examined to understand the quality of the antibody response. METHODS: A testing-on-a-probe "plus" panel (TOP-Plus) was developed to include a newly developed avidity assay built into the previously described SARS-CoV-2 TOP assays that measured total antibody (TAb), surrogate neutralizing antibody (SNAb), IgM, and IgG on a versatile biosensor platform. TAb and SNAb levels were compared with avidity in previously infected individuals at 1.3 and 6.2 months after infection in paired samples from 80 patients with coronavirus disease 2019 (COVID-19). Sera from individuals vaccinated for SARS-CoV-2 were also evaluated for antibody avidity. RESULTS: The newly designed avidity assay in this TOP panel correlated well with a reference Bio-Layer Interferometry avidity assay (r = 0.88). The imprecision of the TOP avidity assay was <10%. Although TAb and neutralization activity (by SNAb) decreased between 1.3 and 6.2 months after infection, the antibody avidity increased significantly (P < 0.0001). Antibody avidity in 10 SARS-CoV-2 vaccinated individuals (median: 28 days after vaccination) was comparable to the measured antibody avidity in infected individuals (median: 26 days after infection). CONCLUSIONS: This highly precise and versatile TOP-Plus panel with the ability to measure SARS-CoV-2 TAb, SNAb, IgG, and IgM antibody levels and avidity of individual sera on one sensor can become a valuable asset in monitoring not only patients infected with SARS-CoV-2 but also the status of individuals' COVID-19 vaccination response.


Subject(s)
Antibodies, Viral/blood , Antibody Affinity/physiology , Biosensing Techniques/methods , COVID-19/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/pathology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Interferometry , Male , Middle Aged , SARS-CoV-2/isolation & purification , Time Factors , Young Adult
18.
Nat Immunol ; 10(9): 1008-17, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19648924

ABSTRACT

Contact-dependent communication between immune cells generates protection but also facilitates viral spread. Here we found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type 1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine-exchange factor-dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients with Nef-deficient virions, our data suggest that HIV-1 exploits intercellular 'highways' as a 'Trojan horse' to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.


Subject(s)
B-Lymphocytes/metabolism , Cell Communication , HIV Antibodies/immunology , HIV-1/immunology , Immunoglobulin A/immunology , Immunoglobulin G/immunology , nef Gene Products, Human Immunodeficiency Virus/physiology , Actins/metabolism , CD40 Antigens/physiology , Germinal Center/physiology , HIV Core Protein p24/physiology , Humans , Immunoglobulin Class Switching , Macrophages/virology , U937 Cells
19.
Haematologica ; 106(3): 730-735, 2021 03 01.
Article in English | MEDLINE | ID: mdl-32107337

ABSTRACT

Four cycles of rituximab plus CHOP chemotherapy is as effective as 6 cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with HIV-associated DLBCL and high-grade lymphoma treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy. 106 evaluable patients with HIV-associated DLBCL or high-grade CD20-positive non-Hodgkin's lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by IV bolus cyclophosphamide every 21 days for 4 to 6 cycles. Patients received 2 additional cycles of therapy after documentation of a complete response (CR) by computerized tomography after cycles 2 and 4. 64 of 106 evaluable patients (60%, 95% CI 50%, 70%) had a CR in both treatment arms. The 2-year event-free survival (EFS) rates were similar in the 24 patients with CR who received 4 or fewer EPOCH cycles (78%, 95% confidence intervals [55%, 90%]) due to achieving a CR after 2 cycles, compared with those who received 5-6 cycles of EPOCH (85%, 95% CI 70%, 93%) because a CR was first documented after cycle 4. A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in patients with HIV-associated lymphoma treated with EPOCH plus rituximab, which merits further evaluation in additional prospective trials. Clinical Trials.gov identifier NCT00049036.


Subject(s)
HIV Infections , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Antineoplastic Combined Chemotherapy Protocols , B-Lymphocytes , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Etoposide/therapeutic use , HIV Infections/drug therapy , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Prednisone/therapeutic use , Prospective Studies , Rituximab/therapeutic use , Vincristine/therapeutic use
20.
Pathobiology ; 88(1): 56-68, 2021.
Article in English | MEDLINE | ID: mdl-32942274

ABSTRACT

BACKGROUND: A novel coronavirus, SARS-CoV-2, was identified in Wuhan, China in late 2019. This virus rapidly spread around the world causing disease ranging from minimal symptoms to severe pneumonia, which was termed coronavirus disease (i.e., COVID). Postmortem examination is a valuable tool for studying the pathobiology of this new infection. METHODS: We report the clinicopathologic findings from 32 autopsy studies conducted on patients who died of COVID-19 including routine gross and microscopic examination with applicable special and immunohistochemical staining techniques. RESULTS: SARS-CoV-2 infection was confirmed by nasopharyngeal RT-PCR in 31 cases (97%) and by immunohistochemical staining for SARS-CoV-2 spike-protein in the lung in the remaining 1 case (3%). The ethnically diverse cohort consisted of 22 males and 10 females with a mean age of 68 years (range: 30-100). Patients most commonly presented with cough (17 [55%]), shortness of breath (26 [81%]), and a low-grade fever (17 [55%]). Thirty-one (97%) of the patients had at least 1 comorbidity (mean = 4). Twenty-eight patients (88%) had widespread thromboembolic disease, as well as diffuse alveolar damage (30 [94%]), diabetic nephropathy (17 [57%]) and acute tubular injury. Patterns of liver injury were heterogeneous, featuring 10 (36%) with frequent large basophilic structures in sinusoidal endothelium, and increased immunoblast-like cells in lymph nodes. CONCLUSION: This series of autopsies from patients with COVID-19 confirms the observation that the majority of severely affected patients have significant pulmonary pathology. However, many patients also have widespread microscopic thromboses, as well as characteristic findings in the liver and lymph nodes.


Subject(s)
COVID-19/virology , Lung/virology , Adult , Aged , Autopsy/methods , COVID-19/pathology , Female , Humans , Lung/pathology , Male , Middle Aged , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
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