Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Laimer, D; Dolznig, H; Kollmann, K; Vesely, PW; Schlederer, M; Merkel, O; Schiefer, AI; Hassler, MR; Heider, S; Amenitsch, L; Thallinger, C; Staber, PB; Simonitsch-Klupp, I; Artaker, M; Lagger, S; Turner, SD; Pileri, S; Piccaluga, PP; Valent, P; Messana, K; Landra, I; Weichhart, T; Knapp, S; Shehata, M; Todaro, M; Sexl, V; Höfler, G; Piva, R; Medico, E; Ruggeri, BA; Cheng, M; Eferl, R; Egger, G; Penninger, JM; Jaeger, U; Moriggl, R; Inghirami, G; Kenner, L.
PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.
Nat Med. 2012; 18(11):1699-1704
Doi: 10.1038/nm.2966
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- Führende Autor*innen der Med Uni Graz
- Kenner Lukas
- Vesely Paul
- Co-Autor*innen der Med Uni Graz
- Höfler Gerald
- Staber Philipp
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- Abstract:
- Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Animals -
- Benzamides -
- Cell Line, Tumor -
- Gene Expression Regulation, Neoplastic - drug effects
- Humans -
- Imatinib Mesylate -
- Lymphoma, Large-Cell, Anaplastic - drug therapy Lymphoma, Large-Cell, Anaplastic - metabolism Lymphoma, Large-Cell, Anaplastic - pathology
- Mice -
- Mice, Transgenic -
- Molecular Targeted Therapy -
- Neoplasm Staging -
- Nuclear Proteins - genetics Nuclear Proteins - metabolism
- Oncogene Protein p65(gag-jun) - genetics Oncogene Protein p65(gag-jun) - metabolism
- Piperazines - administration & dosage
- Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism
- Pyrimidines - administration & dosage
- Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism
- Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors Receptor, Platelet-Derived Growth Factor alpha - genetics Receptor, Platelet-Derived Growth Factor alpha - metabolism
- Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors Receptor, Platelet-Derived Growth Factor beta - genetics Receptor, Platelet-Derived Growth Factor beta - metabolism
- Remission Induction -
- Stem Cell Transplantation -
- Transcription Factor AP-1 - genetics Transcription Factor AP-1 - metabolism
- Translocation, Genetic -