BACKGROUND: Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory. METHODS: We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models. RESULTS: Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients. CONCLUSIONS: These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.

Center of Molecular Medicine Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Haematology Fondazione IRCCS San Gerardo dei Tintori Monza Italy

Department of Medicine and Surgery University of Milano Bicocca Monza Italy

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

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

Department of Pathology Fondazione IRCCS San Gerardo dei Tintori Monza Italy

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge UK

Division of Haematopathology European Institute of Oncology IRCCS Milan Italy

Division of Immunology Transplantation and Infectious Disease IRCCS Ospedale San Raffaele Milano Italy

Faculty of Medicine Masaryk University Brno Czech Republic

Galseq srl Bresso Italy

Maternal and Child Health Department Pediatric Hematology Oncology and Stem Cell Transplant Center University of Padua Padua Italy

Neurogenomics Research Center Fondazione Human Technopole Milano Italy

Pediatric Research Institute Città della Speranza Padua Italy

Weill Cornell Medicine New York NY USA

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