Publications by authors named "Shamzah Araf"

20 Publications

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IGHV sequencing reveals acquired N-glycosylation sites as a clonal and stable event during follicular lymphoma evolution.

Blood 2020 03;135(11):834-844

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

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 attached oligomannoses activate B-cell receptor signaling pathways after engagement with calcium-dependent lectins expressed by tissue macrophages. This novel interaction appears critical for tumor growth and survival. To elucidate the significance of N-gly site presence and loss during ongoing SHM, we tracked site behavior during tumor evolution and progression in a diverse group of patients through next-generation sequencing. A hierarchy of subclones was visualized through lineage trees based on SHM semblance between subclones and their discordance from the germline sequence. We observed conservation of N-gly sites in more than 96% of subclone populations within and across diagnostic, progression, and transformation events. Rare N-gly-negative subclones were lost or negligible from successive events, in contrast to N-gly-positive subclones, which could additionally migrate between anatomical sites. Ongoing SHM of the N-gly sites resulted in subclones with different amino acid compositions across disease events, yet the vast majority of resulting DNA sequences still encoded for an N-gly site. The selection and expansion of only N-gly-positive subclones is evidence of the tumor cells' dependence on sites, despite the changing genomic complexity as the disease progresses. N-gly sites were gained in the earliest identified lymphoma cells, indicating they are an early and stable event of pathogenesis. Targeting the inferred mannose-lectin interaction holds therapeutic promise.
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http://dx.doi.org/10.1182/blood.2019002279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195541PMC
March 2020

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

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

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

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

Epigenetic dysregulation in follicular lymphoma.

Epigenomics 2016 Jan 23;8(1):77-84. Epub 2015 Dec 23.

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.

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 strides are being made in unraveling the biological consequences of these alterations in tumorigenesis opening up new opportunities for directed therapies.
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http://dx.doi.org/10.2217/epi.15.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864036PMC
January 2016

Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.

Nat Genet 2016 Feb 21;48(2):183-8. Epub 2015 Dec 21.

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

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 large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H(+)-ATP ATPase (V-ATPase) known to be necessary for amino acid-induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.
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http://dx.doi.org/10.1038/ng.3473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731318PMC
February 2016

Clinical and laboratory characteristics of acute myeloid leukaemia (AML) at relapse and the risk of acute incapacitation.

J Clin Pathol 2016 Mar 21;69(3):275-6. Epub 2015 Oct 21.

Department of Haemato-Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.

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http://dx.doi.org/10.1136/jclinpath-2015-203332DOI Listing
March 2016

Disease evolution and outcomes in familial AML with germline CEBPA mutations.

Blood 2015 Sep 10;126(10):1214-23. Epub 2015 Jul 10.

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

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.
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http://dx.doi.org/10.1182/blood-2015-05-647172DOI Listing
September 2015

Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

Nat Genet 2014 Feb 22;46(2):176-181. Epub 2013 Dec 22.

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

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 the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.
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http://dx.doi.org/10.1038/ng.2856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907271PMC
February 2014

EZH2 mutations are frequent and represent an early event in follicular lymphoma.

Blood 2013 Oct 19;122(18):3165-8. Epub 2013 Sep 19.

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

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 progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
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http://dx.doi.org/10.1182/blood-2013-04-496893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814734PMC
October 2013

An unusual cause of a haemorrhagic stroke: acquired haemophilia A.

BMJ Case Rep 2013 Jul 5;2013. Epub 2013 Jul 5.

Department of Haematology, Southend University Hospital Foundation Trust, Essex, UK.

An elderly woman presented with extensive bruising and a haemorrhagic stroke. Initial investigations revealed an abnormal clotting screen with a prolonged activated partial thromboplastin time. Further investigations revealed this to be due to antibodies that the patient had developed against clotting factor VIII also known as acquired haemophilia A.
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http://dx.doi.org/10.1136/bcr-2013-010263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736215PMC
July 2013

The use of interim (18)F-fluorodeoxyglucose PET to guide therapy in lymphoma.

Future Oncol 2013 Jun;9(6):807-15

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

Over the past decade (18)F-fluorodeoxyglucose (FDG)-PET combined with computed tomography has gained a central role in the management of patients with lymphoma. The use of FDG-PET for staging and assessing treatment response in Hodgkin's and 'aggressive' non-Hodgkin's lymphoma is now well established, and the prognostic impact of the response to treatment assessed by FDG-PET is being increasingly recognized. Despite the widespread utilization of FDG-PET in clinical practice, key questions remain on its optimal use in certain contexts. One such area that is generating intense interest is the role of interim FDG-PET (typically performed after two to four cycles of chemotherapy) to guide treatment strategies. The author's will review the current available evidence in this area, highlighting questions in need of further study.
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http://dx.doi.org/10.2217/fon.13.55DOI Listing
June 2013

Impact of the revised (2008) EORTC/MSG definitions for invasive fungal disease on the rates of diagnosis of invasive aspergillosis.

Med Mycol 2012 Jul 10;50(5):538-42. Epub 2011 Nov 10.

Department of Haematological Oncology, St Bartholomew's Hospital, London.

Diagnosis of invasive aspergillosis (IA) remains a challenge as the clinical manifestations are not specific, and a histological diagnosis is often unfeasible. The 2002 European Organization for Research and Treatment of Cancer (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria for classification of cases into possible, probable or proven were revised in 2008. Our objective was to analyze the impact of these revisions on the diagnosis of IA. A retrospective analysis of 589 high risk patient-episodes revealed that 125 of 155 'possible' (81%) and 12 of 16 'probable' (75%) cases of IA should be changed to 'non-classifiable' when the new criteria were applied. We concluded, as expected, that the 2008 EORTC/MSG revised definitions reduced the number of cases classified as 'possible' IA, but additionally, there has been a dramatic reduction in 'probable' cases. These changes have significant implications on the interpretation of clinical trial data based on EORTC/MSG classifications.
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http://dx.doi.org/10.3109/13693786.2011.630040DOI Listing
July 2012