Tumor necrosis factor α promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis.

Autor:	Greiner G; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Ihr Labor, Medical Diagnostic Laboratories, Vienna, Austria.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Witzeneder N; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Klein K; Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria., Tangermann S; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria., Kodajova P; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria., Jaeger E; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Ratzinger F; Ihr Labor, Medical Diagnostic Laboratories, Vienna, Austria., Gerner MC; Division of Biomedical Science, University of Applied Sciences FH Campus Wien, Vienna, Austria., Jawhar M; Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.; Department of Hematology and Oncology, Helios Pforzheim, Pforzheim, Germany., Baumgartner S; Department of Pediatrics and Adolescent Medicine, Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University of Vienna, Vienna, Austria., Fruehwirth K; Medical Central Laboratory, State Hospital Feldkirch, Feldkirch, Austria., Schmetterer KG; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Zuber J; Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria., Gleixner KV; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria., Mayerhofer M; Ihr Labor, Medical Diagnostic Laboratories, Vienna, Austria., Schwarzinger I; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Simonitsch-Klupp I; Department of Pathology, Medical University of Vienna, Vienna, Austria., Esterbauer H; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Baer C; Munich Leukemia Laboratory, Munich, Germany., Walter W; Munich Leukemia Laboratory, Munich, Germany., Meggendorfer M; Munich Leukemia Laboratory, Munich, Germany., Strassl R; Division of Clinical Virology, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Haferlach T; Munich Leukemia Laboratory, Munich, Germany., Hartmann K; Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland.; Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland., Kenner L; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria.; Department of Pathology, Medical University of Vienna, Vienna, Austria.; Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria.; Center for Biomarker Research in Medicine, Graz, Austria., Sperr WR; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria., Reiter A; Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany., Sexl V; University of Innsbruck, Innsbruck, Austria., Arock M; Department of Hematological Biology and French National Reference Center for Mastocytosis (CEREMAST), Pitié-Salpêtrière Hospital, Paris Sorbonne University, Paris, France., Valent P; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria., Hoermann G; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Munich Leukemia Laboratory, Munich, Germany.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Mar 14; Vol. 143 (11), pp. 1006-1017.
DOI:	10.1182/blood.2023020515
Abstrakt:	Abstract: Systemic mastocytosis (SM) is defined by the expansion and accumulation of neoplastic mast cells (MCs) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor-independent KIT activation and accumulation of MC. Tumor necrosis factor α (TNF) is a proapoptotic and inflammatory cytokine that has been implicated in the clonal selection of neoplastic cells. We found that KIT D816V increases the expression and secretion of TNF. TNF expression in neoplastic MCs is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation in human BM cells, whereas KIT D816V+ cells are less susceptible to the cytokine, potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of samples from patients with SM. TNF serum levels are significantly elevated in patients with SM and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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