Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Greiner, G; Witzeneder, N; Klein, K; Tangermann, S; Kodajova, P; Jaeger, E; Ratzinger, F; Gerner, MC; Jawhar, M; Baumgartner, S; Fruehwirth, K; Schmetterer, KG; Zuber, J; Gleixner, KV; Mayerhofer, M; Schwarzinger, I; Simonitsch-Klupp, I; Esterbauer, H; Baer, C; Walter, W; Meggendorfer, M; Strassl, R; Haferlach, T; Hartmann, K; Kenner, L; Sperr, WR; Reiter, A; Sexl, V; Arock, M; Valent, P; Hoermann, G.
Tumor necrosis factor α promotes clonal dominance of KIT D816V+cells in mastocytosis: role of survivin and impact on prognosis
BLOOD. 2024; 143(11): 1006-1017.
Doi: 10.1182/blood.2023020515
Web of Science
PubMed
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FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Kenner Lukas
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- Abstract:
- Systemic mastocytosis (SM) is de fi ned 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 alpha (TNF) is a proapoptotic and in fl ammatory 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- kappa B 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 con fi rmed by immunohistochemistry of samples from patients with SM. TNF serum levels are signi fi cantly elevated in patients with SM and high TNF levels were identi fi ed 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 in SM.