Jessica Okosun

• MA MB BChir PhD MRCP FRCPath
• Professor at Barts Cancer Institute

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse...

Introduction: For decades, cancer research has focussed on the genetic defects that drive tumourigenesis. However, recent high-resolution sequencing studies have uncovered mounting evidence for the complementary role of epigenetic deregulation as a hallmark of haematological malignancies. The reversibility of epigenetic changes makes them suitable...

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report...

Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease p...

PURPOSEThe prognosis of HIV-infected patients with non-Hodgkin lymphoma in the highly active antiretroviral therapy (HAART) era approaches that of the general population when they are treated with the same protocols. We analyzed the outcome of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABV...

Significant strides have been made in the treatment of follicular lymphoma, leading to improvements in long‐term patient outcomes. However, the disease's heterogeneity presents challenges in selecting the optimal therapy at each stage of treatment. The expanding array of therapeutic options introduces new complexities, including making the right in...

While the majority of patients with follicular lymphoma (FL) follow an indolent disease course, some patients experience a critical inflection point when FL transforms into an aggressive lymphoma. Historically, FL transformation (tFL) is marked by poor outcomes, particularly for patients with prior FL-directed treatment. Compared to FL, tFL is mark...

Background: Peripheral T-cell lymphomas (PTCL) comprise a group of heterogeneous and aggressive lymphomas, often associated with poor outcomes. Histological heterogeneity and variability in clinical presentation and tissue biopsies are postulated to influence timely diagnoses and outcome, although this has not been formally evaluated. Knowledge of...

Introduction Primary central nervous system lymphoma (PCNSL) is a rare B-cell lymphoma with an aggressive course. We recently identified, double expression of BCL2 and MYC (DE) as a biomarker of aggressive disease in PCNSL (Poynton et al, Blood Advances 2024) but the molecular mechanisms underpinning the adverse prognosis of DE status remain unclea...

Introduction: Scant data exist on prognostic factors, survival and treatment (Tx)-related outcomes in SCNSL. We conducted a multicenter international analysis to identify prognostic factors and outcomes in SCNSL at diagnosis (de novo), or after frontline Tx (1L) either with (concomitant) or without (isolated) systemic (syst) relapse. Methods: This...

Follicular lymphoma (FL) is the second most common type of lymphoma (20% of all non‐Hodgkin lymphomas), derived from germinal centre (GC) B cells, and is characterised by its significant clinical, prognostic and biological heterogeneity, leading to complexity in management. Despite significant biological investigation and indisputable clinical prog...

Despite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker‐directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2‐mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mT...

Analytes within liquid biopsies have emerged as promising alternatives to traditional tissue biopsies for various malignancies, including lymphomas. This review explores the clinical applications of one such liquid biopsy analyte, circulating tumor DNA (ctDNA) in different types of lymphoma, focusing on its role in diagnosis, disease monitoring, an...

Immunoglobulin class-switching from IgM to IgG enhances B cell receptor (BCR) signalling 1,2 and promotes germinal centre (GC) B cell responses to antigens 3,4 . In contrast, non-Hodgkin lymphomas derived from GC B cells typically avoid IgG BCR expression and retain the unswitched IgM BCR, suggesting that the IgG BCR may protect B cells from malign...

Background Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. Methods The REFRACT trial...

Follicular lymphoma is the most common indolent lymphoma accounting for approximately 20%–25% of all new non‐Hodgkin lymphoma diagnoses in western countries. Whilst outcomes are mostly favorable, the spectrum of clinical phenotypes includes high‐risk groups with significantly inferior outcomes. This review discusses recent updates in risk stratific...

Single-cell ribonucleic acid (RNA)-sequencing (scRNA-seq) is a powerful tool to study cellular heterogeneity. The high dimensional data generated from this technology are complex and require specialized expertise for analysis and interpretation. The core of scRNA-seq data analysis contains several key analytical steps, which include pre-processing,...

Diversity, equity, and inclusion (DEI) in research is important. This is the case not only because it is simply the right thing to do but also because DEI fosters collaboration, empathy, and psychological safety between scientists and clinicians as well as in our attitudes to and relations with patients. Inclusion of patient samples from diverse po...

Follicular lymphoma (FL) is a heterogeneous disease, both clinically and biologically. The biological behavior and development of FL is a culmination of complex multistep processes underpinned by genetic and nongenetic determinants. Epigenetic deregulation through recurrent genetic alterations is now a recognized major biological hallmark of FL, al...

Histological transformation (HT) to a more aggressive disease–mostly diffuse large B-cell lymphoma–is considered one of the most dismal events in the clinical course of follicular lymphoma (FL). Current knowledge has not found a single biological event specific for HT, although different studies have highlighted common genetic alterations, such as...

Background Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare disorder with an increasing incidence over the past decades. High-level evidence has been reported for the MATRix regimen (high-dose methotrexate (HD-MTX), high-dose AraC (HD-AraC), thiotepa and rituximab) followed by high-dose chemotherapy and...

Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but falling short of providing a consistent relapse-specific genetic signature. In our study, we have focussed atte...

The optimum management approach for patients with relapsed or refractory (R/R) follicular lymphoma (FL) remains uncertain. Autologous stem cell transplantation (autoSCT) is considered a standard option in suitable, younger patients with relapsed FL. AutoSCT is associated with very durable remissions in a minority but also significant, wellestablish...

In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 iming to highlight achievements in the diagnostics and treatment of blood disorders and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology...

Diffuse large B-cell lymphoma and follicular lymphoma are the most commonly encountered non-Hodgkin lymphomas in clinical practice. Both are biologically heterogeneous, with management strategies that are becoming increasingly complex. Diffuse large B-cell lymphoma typically exhibits aggressive behavior but can be cured in the majority of cases wit...

The development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2...

Introduction Our understanding of the molecular basis of follicular lymphoma (FL) has come a long way since the identification of the reciprocal chromosomal translocation, t(14;18), heralded as the primary genetic hallmark.¹ Over thirty years on, we are approaching a near-complete catalogue of the genetic underpinnings of this lymphoma subtype, pri...

The simultaneous growth in our understanding of lymphoma biology and the burgeoning therapeutic options has come with a renewed drive for precision‐based approaches and how best to incorporate them into contemporary and future patient care. In the hunt for accurate and sensitive biomarkers, liquid biopsies, particularly circulating tumour DNA, have...

Loss-of-function mutations in KMT2D are a striking feature of the germinal centre (GC) lymphomas, resulting in decreased H3K4-methylation and altered gene expression. We hypothesised that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would re-establish H3K4-methylation and restore the expression of genes repressed upon loss of KMT2...

Follicular lymphoma (FL) represents a heterogeneous disease both clinically and biologically. The pathognomonic t(14;18) translocation can no longer be thought of as the primary genetic driver, with increasing recognition of the biological relevance of recurrent genetic alterations in epigenetic regulators that now feature as a pivotal hallmark of...

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL p...

Background: Follicular lymphoma (FL) is an incurable indolent B cell malignancy characterized in the majority of cases by the t(14;18) translocation. While the mutational landscape of the coding genome is nearing completion, less is known about the characteristics of its noncoding genome. Our expectation is that the distribution of noncoding mutati...

Large-scale technology and advanced computational analyses have revolutionized our understanding of the genomic underpinnings of lymphoma subtypes across the board, providing near-complete genomic encyclopedias. A characteristic feature of indolent lymphomas is their propensity to initially respond to therapeutic intervention, only to subsequently...

Loss-of-function mutations in KMT2D are a striking feature of the germinal centre (GC) lymphomas, resulting in decreased H3K4 methylation and altered gene expression. We hypothesised that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would re-establish H3K4 methylation and restore the expression of genes repressed upon loss of KMT2...

Since being identified in China in December 2019, coronavirus disease 2019 (Covid‐19) has rapidly evolved into a global pandemic with over 4 million cases and more than 270,000 deaths.(1) Following the first reported cases in the United Kingdom (UK) in late January 2020, numbers have continued to rise with 223,060 cases and 32,065 deaths reported a...

Although outcomes for follicular lymphoma (FL) continue to improve, it remains incurable for the majority of patients. Through next generation sequencing (NGS) studies, we now recognize that the genomic landscape of FL is skewed toward highly recurrent mutations in genes that encode epigenetic regulators co-occurring with the pathognomonic t(14;18)...

Histologic transformation of follicular lymphoma remains the leading cause of follicular lymphoma-related mortality in the rituximab era. Both the diverse timing of transformation and heterogeneity in associated genomic events suggest that histologic transformation may itself comprise distinct disease entities. Successive indolent and transformatio...

A subset of follicular lymphoma patients with high-risk clinical features continues to pose a therapeutic challenge. Hematopoietic stem cell transplantation is a suitable consolidative treatment option for these patients. Data on chimeric antigen receptor T-cell therapy are promising in relapsed/refractory and transformed patients. The increasing a...

Follicular lymphoma B cells undergo continuous somatic hypermutation (SHM) of their immunoglobulin variable region genes, generating a heterogeneous tumor population. SHM introduces DNA sequences encoding N-glycosylation sites asparagine-X-serine/threonine (N-gly sites) within the V-region that are rarely found in normal B-cell counterparts. Unique...

Background: Although diffuse large B cell lymphoma (DLBCL) can be cured using immuno-chemotherapy, 40% of patients experience relapse or refractory disease. Large-scale profiling studies have mainly focused on DLBCL at diagnosis, resolving different outcome groups based on gene expression (e.g. cell-of-origin (COO) or molecular high grade), MYC/BCL...

The humoral immune response requires that B cells undergo a sudden anabolic shift and high cellular nutrient levels, which are required to sustain the subsequent proliferative burst. Follicular lymphoma (FL) originates from B cells that have participated in the humoral response, and 15% of FL samples harbour point-activating mutations in RRAGC, an...

Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early- and advanced-stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and mo...

In the original version of this article the authors noted an omission in the author affiliations where the university details: Queen Mary University of London was not included in the original affiliation for the majority of the authors. The correct affiliations are as follows 1. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary Univer...

Introduction: Follicular lymphoma (FL) cells retain expression of a functional B cell receptor (BCR) despite the loss of one Ig allele due to the hallmark t14:18 translocation and ongoing somatic hypermutation (SHM) of the variable genes (V genes) which increases the likelihood of crippling mutations. SHM introduces N-glycosylation (N-gly) motifs w...

Purpose of review: The treatment of the germinal center lymphomas, diffuse large B cell (DLBCL) and follicular lymphoma, has changed little beyond the introduction of immunochemotherapies. However, there exists a substantial group of patients within both diseases for which improvements in care will involve appropriate tailoring of treatment. Rece...

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphoma...

Background

Background

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκB, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n 5 1460) diagnosed with differe...

Loss-of-function mutations of the cyclic-AMP response element binding protein, binding protein (CREBBP) gene have recently been described at high frequencies across a spectrum of lymphoid malignancies, particularly follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The multiple effects of this epigenetic regulator on developmental...

Deregulated NF-κB signaling is a hallmark of most, if not all, lymphoid malignancies, and recurrent gene mutations in both the canonical and non-canonical NF-κB pathway are known to lead to NF-κB activation. However, the full compendium of NF-κB gene mutations in lymphoid malignancies remains to be elucidated. Recently, we reported a 4-bp truncatin...

Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis fact...

Purpose of review: Aggressive transformation, a frequent event in the natural history of follicular lymphoma, is associated with increased lymphoma-related mortality and yet the underlying biology remains poorly defined. This review outlines recent advances in our understanding of the genetic basis and evolutionary process leading to transformatio...

The adoption of next-generation sequencing technologies has led to a remarkable shift in our understanding of the genetic landscape of follicular lymphoma. While the disease has been synonymous with the t(14;18), the prevalence of alterations in genes that regulate the epigenome has been established as a pivotal hallmark of these lymphomas. Giant s...

High grade non-Hodgkin lymphoma (NHL) accounts for a significant proportion of lymphoma diagnoses with increasing prevalence and comprised of several distinct pathological entities. The molecular and genetic blueprint for the majority of these lymphomas have recently been unravelled but finer details as to how these molecular abnormalities lead to...

To date, in-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study comprehensively examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germline CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated...

Follicular lymphoma (FL) is the most common type of indolent lymphoma accounting for ~20% of all non-Hodgkins lymphomas or ~1500 new cases annually in the UK. Although essentially a chronic malignancy, 30-40% of FL patients undergo histological transformation to a much more aggressive lymphoma drastically reducing the median overall survival from 1...

Background: Follicular lymphoma (FL) and the germinal centre B-cell (GCB) subtype of diffuse large B cell lymphoma (GCB-DLBCL) account for nearly 40- 50% of cases of Non-Hodgkin lymphomas (NHL). Whole exome and targeted resequencing studies demonstrated an epigenetic addiction in these germinal centre lymphomas with many biopsies harbouring mutatio...

Introduction Genetic aberrations of Tumor Necrosis Factor Receptor Superfamily 14 (TNFRSF14, also known as HVEM) have been shown to occur at high frequencies in patients (pts) with follicular lymphoma (FL). HVEM is a ligand for B and T lymphocyte attenuator (BTLA) which negatively regulates T cell responses and BTLA stimulation reduces acute graft-...