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Selected Publication:

Type of publication: Journal Article
Type of document: Full Paper

Year: 2012

Authors: 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

Title: PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.

Source: Nat Med. 2012; 18(11):1699-1704



Authors Vetmeduni Vienna:

Kenner Lukas
Kollmann Karoline
Lagger Sabine
Moriggl Richard
Sexl Veronika

Vetmed Research Units
Institute of Pharmacology and Toxicology


Project(s): CDK6 - ein therapeutischer Angriffspunkt in Leukämien?


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.

Keywords Pubmed: Adult
Animals
Benzamides
Cell Line, Tumor
Gene Expression Regulation, Neoplastic/drug effects
Humans
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


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