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 inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

Center for Biomarker Research in Medicine Vienna Core Lab2 Medical University of Vienna Vienna Austria

Central European Institute of Technology Masaryk University Brno Czech Republic

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Department of Clinical Research Gustave Roussy Cancer Center Villejuif France

Department of Experimental Pathology and Laboratory Animal Pathology Institute of Clinical Pathology Medical University of Vienna Vienna Austria

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of Medicine Columbia Center for Human Development Columbia University Irving Medical Center New York NY

Department of Molecular Biotechnology and Health Sciences University of Torino Torino Italy

Department of Pathology and Laboratory Medicine Aga Khan University Hospital Karachi Pakistan

Department of Pathology Boston Children's Hospital and Harvard Medical School Boston MA

Department of Pathology CHU Necker Enfants Malades Paris France

Department of Pathology Hematopathology Section Universitätsklinikum Schleswig Holstein Campus Kiel Kiel Germany

Department of Pediatric Adolescent and Young Adult Oncology Institute Curie Medical Centre Paris France

Department of Pediatric and Adolescent Oncology Gustave Roussy Cancer Center Villejuif France; and

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Medical University of Vienna Vienna Austria

Department of Pediatric Hematology and Oncology University Hospital Hamburg Eppendorf Hamburg Germany

Department of Pediatric Hematology Oncology and Palliative Care Addenbrooke's Hospital Cambridge University Hospitals National Health Service Foundation Trust Cambridge United Kingdom

Department of Pediatric Oncology and Hematology Sorbonne Université Trousseau Hospital Assistance Publique Hôpitaux de Paris Paris France

Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge United Kingdom

Equipe Integrated Cancer Research Site Institut Curie Paris France

European Molecular Biology Laboratory European Bioinformatics Institute Hinxton Cambridge United Kingdom

Experimental and Laboratory Animal Pathology Department of Pathology Medical University of Vienna Vienna Austria

INSERM U1015 Université Paris Saclay Villejuif France

INSERM U830 Transfer Department Laboratoire de Génétique et Biologie des Cancers Institut Curie Paris France

Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen University Hospital Tübingen Eberhard Karls University Tübingen Germany

Oncology Center SIREDO Institut Curie Paris France

School of Biomedical Sciences Li Ka Shing Faculty of Medicine The University of Hong Kong Pokfulam Hong Kong China

School of Medicine and Surgery University of Milano Bicocca Monza Italy

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

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Blood. 2020 Oct 1;136(14):1573-1575. doi: 10.1182/blood.2020007226. PubMed

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Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma

STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma

Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib

Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma

Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma

BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL

Resistance to Targeted Agents Used to Treat Paediatric ALK-Positive ALCL