Publications by authors named "Jude Fitzgibbon"

85 Publications

Germline ETV6 variants: not ALL created equally.

Blood 2021 Jan;137(3):288-289

Queen Mary University of London.

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http://dx.doi.org/10.1182/blood.2020008190DOI Listing
January 2021

Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma.

Int J Mol Sci 2020 Nov 20;21(22). Epub 2020 Nov 20.

Molecular Oncology Group, Biodonostia Research Institute, 20014 San Sebastián, Spain.

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 patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in and genes impaired the binding efficiency of and and regulated the endogenous levels of messenger RNA (mRNA).
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http://dx.doi.org/10.3390/ijms21228795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699894PMC
November 2020

A frameshift variant in specificity protein 1 triggers superactivation of Sp1-mediated transcription in familial bone marrow failure.

Proc Natl Acad Sci U S A 2020 07 7;117(29):17151-17155. Epub 2020 Jul 7.

Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT London, United Kingdom.

Inherited bone marrow failure (BMF) syndromes are a heterogeneous group of diseases characterized by defective hematopoiesis and often predisposing to myelodysplastic syndrome (MDS) and acute myelogenous leukemia. We have studied a large family consisting of several affected individuals with hematologic abnormalities, including one family member who died of acute leukemia. By whole-exome sequencing, we identified a novel frameshift variant in the ubiquitously expressed transcription factor specificity protein 1 (). This heterozygous variant (c.1995delA) truncates the canonical Sp1 molecule in the highly conserved C-terminal DNA-binding zinc finger domains. Transcriptomic analysis and gene promoter characterization in patients' blood revealed a hypermorphic effect of this Sp1 variant, triggering superactivation of Sp1-mediated transcription and driving significant up-regulation of Sp1 target genes. This familial genetic study indicates a central role for Sp1 in causing autosomal dominant transmission of BMF, thereby confirming its critical role in hematopoiesis in humans.
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http://dx.doi.org/10.1073/pnas.2002857117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382244PMC
July 2020

The Biological Basis of Histologic Transformation.

Hematol Oncol Clin North Am 2020 08 5;34(4):771-784. Epub 2020 May 5.

Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: https://twitter.com/fitzgi02.

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 transformation episodes occur by divergent clonal evolution from an inferred common progenitor cell, representing a potential therapeutic target. Existing biological knowledge largely pre-dates anti-CD20 therapy, and further prospective validation is essential. Inclusion of transformation cases in clinical trials incorporating biomarker discovery, and an integrated understanding of the genetic and microenvironmental factors underpinning transformation, may unearth renewed clinical opportunities.
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http://dx.doi.org/10.1016/j.hoc.2020.02.010DOI Listing
August 2020

Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia.

J Clin Invest 2020 06;130(6):3038-3050

Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, United Kingdom.

Acute myeloid leukemia (AML) disrupts the generation of normal blood cells, predisposing patients to hemorrhage, anemia, and infections. Differentiation and proliferation of residual normal hematopoietic stem and progenitor cells (HSPCs) are impeded in AML-infiltrated bone marrow (BM). The underlying mechanisms and interactions of residual hematopoietic stem cells (HSCs) within the leukemic niche are poorly understood, especially in the human context. To mimic AML infiltration and dissect the cellular crosstalk in human BM, we established humanized ex vivo and in vivo niche models comprising AML cells, normal HSPCs, and mesenchymal stromal cells (MSCs). Both models replicated the suppression of phenotypically defined HSPC differentiation without affecting their viability. As occurs in AML patients, the majority of HSPCs were quiescent and showed enrichment of functional HSCs. HSPC suppression was largely dependent on secreted factors produced by transcriptionally remodeled MSCs. Secretome analysis and functional validation revealed MSC-derived stanniocalcin 1 (STC1) and its transcriptional regulator HIF-1α as limiting factors for HSPC proliferation. Abrogation of either STC1 or HIF-1α alleviated HSPC suppression by AML. This study provides a humanized model to study the crosstalk among HSPCs, leukemia, and their MSC niche, and a molecular mechanism whereby AML impairs normal hematopoiesis by remodeling the mesenchymal niche.
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http://dx.doi.org/10.1172/JCI133187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260026PMC
June 2020

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants.

Nat Commun 2020 02 25;11(1):1044. Epub 2020 Feb 25.

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
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http://dx.doi.org/10.1038/s41467-020-14829-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042299PMC
February 2020

AML through the prism of molecular genetics.

Br J Haematol 2020 01;188(1):49-62

Centre for Haemato-oncology, Barts Cancer Institute, QMUL, London, UK.

Modern management of acute myeloid leukaemia (AML) relies on the integration of phenotypic and genetic data to assign classification, establish prognosis, enhance monitoring and guide treatment. The prism through which we can now disperse a patient's leukaemia, interpret and apply our understanding has fundamentally changed since the completion of the first whole-genome sequencing (WGS) of an AML patient in 2008 and where possible, many clinicians would now prefer to delay treatment decisions until the karyotype and genetic status of a new patient is known. The success of global sequencing initiatives such as The Cancer Genome Atlas (TCGA) have brought us significantly closer to cataloguing the full spectrum of coding mutations involved in human malignancy. Indeed, genetic capability has raced ahead of our capacity to apply much of this knowledge into clinical practice and we are in the peculiar position of having routine access to genetic information on an individual patient's leukaemia that cannot be reliably interpreted or utilised. This is a measure of how rapid the progress has been, and this rate of change is likely to continue into the foreseeable future as research intensifies on the non-coding genome and the epigenome, as we scrutinise disease at a single cell level, and as initiatives like Beat AML and the Harmony Alliance progress. In this review, we will examine how interrogation of the coding genome is revolutionising our understanding of AML and improving our ability to underscore differences between paediatric and adult onset, sporadic and inherited forms of disease. We will look at how this knowledge is informing improvements in outcome prediction and the development of novel treatments, bringing us a step closer to personalised therapy for myeloid malignancy.
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http://dx.doi.org/10.1111/bjh.16356DOI Listing
January 2020

Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit.

Leukemia 2020 05 16;34(5):1329-1341. Epub 2019 Dec 16.

Department of Pathology, University of Cambridge, Cambridge, UK.

Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.
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http://dx.doi.org/10.1038/s41375-019-0691-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192846PMC
May 2020

Follicular lymphoma.

Nat Rev Dis Primers 2019 12 12;5(1):83. Epub 2019 Dec 12.

Barts Cancer Institute, Queen Mary University of London, London, UK.

Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue displaying germinal centre (GC) B cell differentiation. FL represents ~5% of all haematological neoplasms and ~20-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Tumorigenesis starts in precursor B cells and becomes full-blown tumour when the cells reach the GC maturation step. FL is preceded by an asymptomatic preclinical phase in which premalignant B cells carrying a t(14;18) chromosomal translocation accumulate additional genetic alterations, although not all of these cells progress to the tumour phase. FL is an indolent lymphoma with largely favourable outcomes, although a fraction of patients is at risk of disease progression and adverse outcomes. Outcomes for FL in the rituximab era are encouraging, with ~80% of patients having an overall survival of >10 years. Patients with relapsed FL have a wide range of treatment options, including several chemoimmunotherapy regimens, phosphoinositide 3-kinase inhibitors, and lenalidomide plus rituximab. Promising new treatment approaches include epigenetic therapeutics and immune approaches such as chimeric antigen receptor T cell therapy. The identification of patients at high risk who require alternative therapies to the current standard of care is a growing need that will help direct clinical trial research. This Primer discusses the epidemiology of FL, its molecular and cellular pathogenesis and its diagnosis, classification and treatment.
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http://dx.doi.org/10.1038/s41572-019-0132-xDOI Listing
December 2019

Oncogenic Rag GTPase signaling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR.

Nat Metab 2019 08 19;1(8):775-789. Epub 2019 Aug 19.

Metabolism and Cell Signaling Laboratory. Spanish National Cancer Research Center (CNIO). Madrid, Spain.

The humoral immune response demands 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 harbor point, activating mutations in , an essential activator of mTORC1 downstream of the sensing of cellular nutrients. The impact of recurrent mutations in B cell function and lymphoma is unexplored. mutations, targeted to the endogenous locus in mice, confer a partial insensitivity to nutrient deprivation, but strongly exacerbate B cell responses and accelerate lymphomagenesis, while creating a selective vulnerability to pharmacological inhibition of mTORC1. This moderate increase in nutrient signaling synergizes with paracrine cues from the supportive T cell microenvironment that activates B cells via the PI3K-Akt-mTORC1 axis. Hence, mutations sustain induced germinal centers and murine and human FL in the presence of decreased T cell help. Our results support a model in which activating mutations in the nutrient signaling pathway foster lymphomagenesis by corrupting a nutrient-dependent control over paracrine signals from the T cell microenvironment.
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http://dx.doi.org/10.1038/s42255-019-0098-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774795PMC
August 2019

Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML.

Sci Adv 2019 07 10;5(7):eaaw4304. Epub 2019 Jul 10.

The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human mutant AML and the corresponding mouse model, we identified , encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target.
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http://dx.doi.org/10.1126/sciadv.aaw4304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620102PMC
July 2019

Correction: Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma.

Leukemia 2019 Jun;33(6):1540

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

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 follows1. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK3. Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK6. Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, London, UK.
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http://dx.doi.org/10.1038/s41375-019-0425-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608209PMC
June 2019

Rituximab as a first step in tackling transformation.

Lancet Haematol 2018 08 4;5(8):e326-e327. Epub 2018 Jul 4.

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

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http://dx.doi.org/10.1016/S2352-3026(18)30093-0DOI Listing
August 2018

Precision medicine and lymphoma.

Curr Opin Hematol 2018 07;25(4):329-334

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

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.

Recent Findings: DLBCL consists of two major subtypes with striking differences in their clinical outcomes paralleling their underlying genetic heterogeneity. Recent studies have seen advances in the stratification of germinal center lymphomas, through comprehensive profiling of 1001 DLBCLs alongside refinements in the identification of high-risk follicular lymphoma patients using m7-FLIPI and 23G models. A new wave of novel therapeutic agents is now undergoing clinical trials for germinal center lymphomas, with BCR and EZH2 inhibitors demonstrating preferential benefit in subgroups of patients. The emergence of cell-free DNA has raised the possibility of dynamic disease monitoring to potentially mitigate the complexity of spatial and temporal heterogeneity, whilst predicting tumor evolution in real time.

Summary: Altogether knowledge of the genomic landscape of germinal center lymphomas is offering welcome opportunities in patient risk stratification and therapeutics. The challenge ahead is to establish how best to combine upfront or dynamic prognostication with precision therapies, while retaining practicality in clinical trials and the real-world setting.
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http://dx.doi.org/10.1097/MOH.0000000000000437DOI Listing
July 2018

Predicting early relapse in follicular lymphoma: have we turned a corner?

Lancet Oncol 2018 04 20;19(4):441-442. Epub 2018 Feb 20.

Centre for Haemato-Oncology, Barts Cancer Institute, London EC1M 6BQ, UK. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(18)30114-1DOI Listing
April 2018

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

Nat Cell Biol 2017 Sep 21;19(9):1093-1104. Epub 2017 Aug 21.

Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, UK.

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 lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.
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http://dx.doi.org/10.1038/ncb3597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633079PMC
September 2017

Familial CEBPA-mutated acute myeloid leukemia.

Semin Hematol 2017 04 7;54(2):87-93. Epub 2017 Apr 7.

Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom.

Familial CEBPA-mutated acute myeloid leukemia (AML) represents a recognized leukemia predisposition syndrome, with several families described in the literature since the initial report in 2004. The pathological features and long-term survival of individuals with familial CEBPA-mutated AML are reminiscent of sporadic CEBPAdm AML.  Germline mutations predominantly localize to the N-terminal and are associated with near complete penetrance, with age of AML onset from 2-50 years, frequently accompanied by the acquisition of a second CEBPA mutation in C-terminal domain.  Patients appear to have a significant risk of late AML recurrence and these typically represent independent leukemic episodes, characterized by a unique molecular profile that is distinct from that of the preceding tumor.  While these patients respond well to salvage therapies, allogeneic hematopoietic stem cell transplantation (HSCT) should be considered for patients with high-risk features at presentation or recurrent disease, with the aim of eradicating the germline mutation and improving long-term survival. In contrast, inherited C-terminal CEBPA mutations occur less frequently and appear to demonstrate reduced penetrance, impeding clinical detection and surveillance.
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http://dx.doi.org/10.1053/j.seminhematol.2017.04.001DOI Listing
April 2017

Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree.

Eur J Hum Genet 2017 08 17;25(8):1020-1024. Epub 2017 May 17.

1st Department of Pathology and Experimental Cancer Research, MTA-SE Lendulet Molecular Oncohematology Research Group, Semmelweis University, Budapest, Hungary.

Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.
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http://dx.doi.org/10.1038/ejhg.2017.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567149PMC
August 2017

Follicular lymphoma: State-of-the-art ICML workshop in Lugano 2015.

Hematol Oncol 2017 Dec 4;35(4):397-407. Epub 2017 Apr 4.

Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland.

The 13th International Conference on Malignant Lymphoma held in Lugano in June 2015 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) with the aim of developing an up-to-date understanding of the biology of follicular lymphoma and the clinical implications of new findings in the field. Discussed topics included the mutational spectrum at diagnosis, the clinical correlates of genetic and epigenetic alterations, the mechanisms of clonal evolution and histological transformation, the cross talk between tumor cells and microenvironment, and the development of novel treatments. This report represents a summary of the workshop.
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http://dx.doi.org/10.1002/hon.2411DOI Listing
December 2017

Follicular lymphoma, a B cell malignancy addicted to epigenetic mutations.

Epigenetics 2017 05 20;12(5):370-377. Epub 2017 Jan 20.

a Centre for Haemato-Oncology, Barts Cancer Institute , Queen Mary University of London , London , United Kingdom.

While follicular lymphoma (FL) is exquisitely responsive to immuno-chemotherapy, many patients follow a relapsing remitting clinical course driven in part by a common precursor cell (CPC) population. Advances in next generation sequencing have provided valuable insights into the genetic landscape of FL and its clonal evolution in response to therapy, implicating perturbations of epigenetic regulators as a hallmark of the disease. Recurrent mutations of histone modifiers KMT2D, CREBBP, EP300, EZH2, ARIDIA, and linker histones are likely early events arising in the CPC pool, rendering epigenetic based therapies conceptually attractive for treatment of indolent and transformed FL. This review provides a synopsis of the main epigenetic aberrations and the current efforts in development and testing of epigenetic therapies in this B cell malignancy.
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http://dx.doi.org/10.1080/15592294.2017.1282587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453190PMC
May 2017

Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma.

Blood 2016 12 26;128(23):2666-2670. Epub 2016 Sep 26.

Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, 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 = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.
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http://dx.doi.org/10.1182/blood-2016-03-704528DOI Listing
December 2016

Advances in the molecular diagnosis of diffuse large B-cell lymphoma in the era of precision medicine.

Expert Rev Mol Diagn 2016 10 24;16(10):1093-1102. Epub 2016 Sep 24.

a Centre for Haemato-Oncology , Barts Cancer Institute, Queen Mary University of London , London , UK.

Introduction: The adoption of high-throughput technologies has led to a transformation in our ability to classify diffuse large B-cell lymphoma (DLBCL) into unique molecular subtypes. In parallel, the expansion of agents targeting key genetic and gene expression signatures has led to an unprecedented opportunity to personalize cancer therapies, paving the way for precision medicine. Areas covered: This review summarizes the key molecular subtypes of DLBCL and outlines the novel technology platforms in development to discriminate clinically relevant subtypes. Expert commentary: The application of emerging diagnostic tests into routine clinical practise is gaining momentum following the demonstration of subtype specific activity by novel agents. Co-ordinated efforts are required to ensure that these state of the art technologies provide reliable and clinically meaningful results accessible to the wider haematology community.
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http://dx.doi.org/10.1080/14737159.2016.1235974DOI Listing
October 2016

Pediatric-type FL: simply different.

Blood 2016 08;128(8):1030-1

QUEEN MARY UNIVERSITY OF LONDON.

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http://dx.doi.org/10.1182/blood-2016-07-725002DOI Listing
August 2016