DEK regulates B-cell proliferative capacity and is associated with aggressive disease in low-grade B-cell lymphomas.

This study sheds light on the pivotal role of the oncoprotein DEK in B-cell lymphoma. We reveal DEK expression correlates with increased tumor proliferation and inferior overall survival in cases diagnosed with low-grade B-cell lymphoma (LGBCL). We also found significant correlation between DEK expression and copy number alterations in LGBCL tumors, highlighting a novel mechanism of LGBCL pathogenesis that warrants additional exploration.

Long-term effects of a lifestyle modification program for men with obesity delivered in German football clubs.

This study examined the long-term effects of a lifestyle modification program delivered at German Bundesliga football clubs. Weekly 90-minute group sessions over 12 weeks combined health education and physical activity and were delivered by coaches affiliated with the football clubs. A total of 371 men (mean age 49.

Multiomics analysis of IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation.

Currently, the role of DNA methylation in the immunoglobulin M (IgM) monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenström macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS.

Monocyte response to SARS-CoV-2 protein ORF8 is associated with severe COVID-19 infection in patients with chronic lymphocytic leukemia.

The open reading frame 8 (ORF8) protein, encoded by the SARS-CoV-2 virus after infection, stimulates monocytes/macrophages to produce pro-inflammatory cytokines. We hypothesized that a positive ex vivo monocyte response to ORF8 protein pre-COVID-19 would be associated with subsequent severe Coronavirus disease 2019 (COVID-19). We tested ORF8 ex vivo on peripheral blood mononuclear cells from 26 anonymous healthy blood donors and measured intracellular cytokine/ chemokine levels in monocytes by flow cytometry.

Follicular lymphoma B cells exhibit heterogeneous transcriptional states with associated somatic alterations and tumor microenvironments.

Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma of germinal center origin, which presents with significant biologic and clinical heterogeneity. Using RNA-seq on B cells sorted from 87 FL biopsies, combined with machine-learning approaches, we identify 3 transcriptional states that divide the biological ontology of FL B cells into inflamed, proliferative, and chromatin-modifying states, with relationship to prior GC B cell phenotypes. When integrated with whole-exome sequencing and immune profiling, we find that each state was associated with a combination of mutations in chromatin modifiers, copy-number alterations to TNFAIP3, and T follicular helper cells (Tfh) cell interactions, or primarily by a microenvironment rich in activated T cells.

Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-19.

Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein and in symptomatic patients with COVID-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14 monocytes to induce inflammasomal cytokine/chemokine responses including IL1β, IL8, and CCL2.

Molecular classification and identification of an aggressive signature in low-grade B-cell lymphomas.

Non-follicular low-grade B-cell lymphomas (LGBCL) are biologically diverse entities that share clinical and histologic features that make definitive pathologic categorization challenging. While most patients with LGBCL have an indolent course, some experience aggressive disease, highlighting additional heterogeneity across these subtypes. To investigate the potential for shared biology across subtypes, we performed RNA sequencing and applied machine learning approaches that identified five clusters of patients that grouped independently of subtype.

Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen-activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1R ) that resulted in refractory ECD affecting the central nervous system.

MCIR1: A patient-derived mantle cell lymphoma line for discovering new treatments for ibrutinib resistance.

Background: Despite the unprecedented success of ibrutinib in lymphoma therapy, the development of ibrutinib resistance due to acquired BTK or PLCγ2 mutations has become a new clinical problem. However, not all resistance is mediated by these mutations and these mechanisms are poorly understood due to a lack of study tools that truly recapitulate this clinical scenario.

Methods: We established a novel patient-derived ibrutinib-resistant mantle cell lymphoma (MCL) line named MCIR1.

Somatic copy number gains in MYC, BCL2, and BCL6 identifies a subset of aggressive alternative-DH/TH DLBCL patients.

Double/triple hit lymphoma (DH/TH), known as high-grade B-cell lymphoma (HGBL), is an aggressive diffuse large B cell lymphoma (DLBCL), defined as having concurrent MYC, BCL2, and/or BCL6 gene rearrangements. While gene rearrangements represent significant genetic events in cancer, copy number alterations (CNAs) also play an important role, and their contributions to rearrangements have yet to be fully elucidated. Using FISH and high-resolution CNA data, we defined the landscape of concurrent gene rearrangements and copy gains in MYC, BCL2, and BCL6, in a cohort of 479 newly diagnosed DLBCL.

Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and front line therapies have not improved overall outcomes since the advent of immunochemotherapy. By pairing DNA and gene expression data with clinical response data, we identified a high-risk subset of non-GCB DLBCL patients characterized by genomic alterations and expression signatures capable of sustaining an inflammatory environment. These mutational alterations (PIM1, SPEN, and MYD88 [L265P]) and expression signatures (NF-κB, IRF4, and JAK-STAT engagement) were associated with proliferative signaling, and were found to be enriched in patients treated with RCHOP that experienced unfavorable outcomes.

Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes.

Ibrutinib-related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment-naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off-study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major-response rate (MRR) was 78%.

Loss of TNFAIP3 enhances MYD88-driven signaling in non-Hodgkin lymphoma.

MYD88 mutations are one of the most recurrent mutations in hematologic malignancies. However, recent mouse models suggest that MYD88 alone may not be sufficient to induce tumor formation. Interplay between MYD88 and other genetic events is further supported by the fact that TNFAIP3 (A20) inactivation often accompanies MYD88.

B-cell activating factor-receptor specific activation of tumor necrosis factor receptor associated factor 6 and the phosphatidyl inositol 3-kinase pathway in lymphoma B cells.

B-cell activating factor-receptor (BAFF-R) is the primary BAFF receptor that is responsible for promoting B-cell development and survival. Malignant B-cells exploit the BAFF/BAFF-R system, and high serum BAFF levels or genetic alterations in BAFF receptors have been found in B-cell cancers. BAFF signaling impacts pro-survival pathways.

t(X;14)(p11;q32) in MALT lymphoma involving GPR34 reveals a role for GPR34 in tumor cell growth.

Genetic aberrations, including trisomies 3 and 18, and well-defined IGH translocations, have been described in marginal zone lymphomas (MZLs); however, these known genetic events are present in only a subset of cases. Here, we report the cloning of an IGH translocation partner on chromosome X, t(X;14)(p11.4;q32) that deregulates expression of an poorly characterized orphan G-protein-coupled receptor, GPR34.

A reappraisal of immunoglobulin variable gene primers and its impact on assessing clonal relationships between PB B cells and BM plasma cells in AL amyloidosis.

Monoclonal tumor plasma cells as well as non-terminally differentiated B cells having a clonal relationship to the tumor cells have been detected in the peripheral blood (PB) of some multiple myeloma (MM) patients but rarely in light chain (primary systemic) amyloidosis (AL) patients. Previously, our group found these peripheral clonotypic B cells in three AL patients. Here, we report detailed analysis of a larger cohort of AL patients to validate the prior findings and to investigate the effect of this cell population on clinical outcome.

Soluble IL-2Rα facilitates IL-2-mediated immune responses and predicts reduced survival in follicular B-cell non-Hodgkin lymphoma.

Elevated serum levels of the soluble form of IL-2 receptor α (sIL-2Rα) have been correlated with a poor prognosis in a variety of different types of cancers. However, its biologic relevance remains unclear and controversial. In patients with follicular B-cell non-Hodgkin lymphoma (FL), we observed that serum sIL-2Rα levels were elevated compared with controls and that elevated sIL-2Rα levels before treatment were associated with a poor outcome.

Establishment and characterization of a novel Waldenstrom macroglobulinemia cell line, MWCL-1.

Waldenström macroglobulinemia (WM) is a rare, lymphoplasmacytic lymphoma characterized by hypersecretion of immunoglobulin M (IgM) protein and tumor infiltration into the bone marrow and lymphatic tissue. Our understanding of the mechanisms driving the development and progression of WM is currently by the shortage of representative cell models available for study. We describe here the establishment of a new WM cell line, MWCL-1.

Utility of Doppler myocardial imaging, cardiac biomarkers, and clonal immunoglobulin genes to assess left ventricular performance and stratify risk following peripheral blood stem cell transplantation in patients with systemic light chain amyloidosis (Al).

Background: Cardiac dysfunction is a well-recognized complication of light chain amyloidosis (AL). Autologous stem cell transplant (auto-SCT) has emerged as a successful treatment modality for AL patients. In this study, we examined the effect of clonal immunoglobulin light chain genes (VL), which encodes the immunoglobulin light chain protein that ultimately forms amyloid, on cardiac function, in the context of auto-SCT and its impact on overall survival.

A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling.

The cytokine B cell activating factor (BAFF) and its receptor, BAFF receptor (BAFF-R), modulate signaling cascades critical for B cell development and survival. We identified a novel mutation in TNFRSF13C, the gene encoding human BAFF-R, that is present in both tumor and germline tissue from a subset of patients with non-Hodgkin lymphoma. This mutation encodes a His159Tyr substitution in the cytoplasmic tail of BAFF-R adjacent to the TRAF3 binding motif.

Genetic variation in B-cell-activating factor is associated with an increased risk of developing B-cell non-Hodgkin lymphoma.

Elevated B-cell-activating factor (BAFF; TNFSF13B) levels have been found in patients with B-cell malignancies and autoimmune diseases, suggesting that it may play a pathogenic role. We previously found that a single nucleotide polymorphism (SNP) in the TNFSF13B promoter resulted in increased transcription, suggesting that genetic variation in TNFSF13B may influence its expression. We therefore wanted to determine if genetic variation in TNFSF13B is associated with high BAFF levels and non-Hogkin lymphoma (NHL) risk.