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Non-Hodgkin Lymphoma
Whole exome sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target
Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1693-1704
Hugo Larose,1,2 Nina Prokoph,1,2 Jamie D. Matthews,1 Michaela Schlederer,3 Sandra Högler,4 Ali F. Alsulami,5 Stephen P. Ducray,1,2 Edem Nuglozeh,6 Mohammad Feroze Fazaludeen,7 Ahmed Elmouna,6 Monica Ceccon,2,8 Luca Mologni,2,8 Carlo Gambacorti-Passerini,2,8 Gerald Hoefler,9 Cosimo Lobello,2,10 Sarka Pospisilova,2,10,11 Andrea Janikova,2,11 Wilhelm Woessmann,2,12 Christine Damm-Welk,2,12 Martin Zimmermann,13 Alina Fedorova,14 Andrea Malone,15 Owen Smith,15 Mariusz Wasik,2,16 Giorgio Inghirami,17 Laurence Lamant,18
Tom L. Blundell,5 Wolfram Klapper,19 Olaf Merkel,2,3 G. A. Amos Burke,20 Shahid Mian,6 Ibraheem Ashankyty,21 Lukas Kenner2,3,22
and Suzanne D. Turner1,2,10
1Department of Pathology, University of Cambridge, Cambridge, UK; 2European Research Initiative for ALK Related Malignancies (ERIA; www.ERIALCL.net); 3Department of Pathology, Medical University of Vienna, Vienna, Austria; 4Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria; 5Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK; 6Molecular Diagnostics and Personalised Therapeutics Unit, Colleges of Medicine and Applied Medical Sciences, University of Ha’il, Ha’il, Saudi Arabia; 7Neuroinflammation Research Group, Department of Neurobiology, A.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland; 8University of Milano-Bicocca, Monza, Italy ; 9Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria ; 10Center of Molecular Medicine, CEITEC, Masaryk University, Brno, Czech Republic; 11Department of Internal Medicine – Hematology and Oncology, University Hospital Brno, Czech Republic; 12University Hospital Hamburg-Eppendorf, Pediatric Hematology and Oncology, Hamburg, Germany; 13Department of Pediatric Hematology/Oncology and Blood Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; 14Belarusian Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus; 15Our Lady’s Children’s Hospital, Crumlin, Ireland; 16Perelman School of Medicine, Philadelphia, PA, USA; 17Department of Pathology and Laboratory Medicine, Cornell University, New York, NY USA; 18Institut Universitaire du Cancer Toulouse, Oncopole et Université Paul-Sabatier, Toulouse, France; 19Department of Pathology, Hematopathology Section, UKSH Campus Kiel, Kiel, Germany; 20Department of Paediatric Oncology, Addenbrooke’s Hospital, Cambridge, UK; 21Department of Medical Technology Laboratory, College of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia and 22Ludwig-Boltzmann Institute for Cancer Research, Vienna, Austria
ABSTRACT
Patients diagnosed with anaplastic large cell lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, we performed whole-exome sequencing of anaplastic lymphoma kinase (ALK)+ ALCL, as well as gene-set enrichment analysis. This revealed that the T-cell receptor and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK– ALCL patients’ samples. Furthermore, we demon- strated that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ- secretase inhibitors or silencing by short hairpin RNA leads to apoptosis; co- treatment in vitro with the ALK inhibitor crizotinib led to additive/synergistic antitumor activity suggesting that this may be an appropriate combination
Correspondence:
SUZANNE D. TURNER
sdt36@cam.ac.uk
Received: September 19, 2019. Accepted: April 9, 2020. Pre-published: April 23, 2020.
https://doi.org/10.3324/haematol.2019.238766
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