Genome-wide CRISPR activation and knockout screens identify genes involved in modulating sensitivity to crizotinib in NPM1-ALK+ ALCL.
Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor–relapsed patient tumors, we show that resistance to ALK inhibitio..... READ ARTICLE
Blood DOI:10.1182/blood.2019003793
Authors: Nina Prokoph, Nicola A. Probst, Liam C. Lee, Jack M. Monahan, Jamie D. Matthews, Huan-Chang Liang, Klaas Bahnsen, Ivonne A. Montes-Mojarro, Elif Karaca-Atabay, Geeta G. Sharma, Vikas Malik, Hugo Larose, Sorcha D. Forde, Stephen P. Ducray, Cosimo Lobello, Qi Wang, Shi-Lu Luan, Šárka Pospíšilová, Carlo Gambacorti-Passerini, G. A. Amos Burke, Shahid Pervez, Andishe Attarbaschi, Andrea Janíková, Hélène Pacquement, Judith Landman-Parker, Anne Lambilliotte, Gudrun Schleiermacher, Wolfram Klapper, Ralf Jauch, Wilhelm Woessmann, Gilles Vassal, Lukas Kenner, Olaf Merkel, Luca Mologni, Roberto Chiarle, Laurence Brugières, Birgit Geoerger, Isaia Barbieri and Suzanne D. Turner
