| Title | PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas. |
| Publication Type | Journal Article |
| Year of Publication | 2012 |
| Authors | Laimer D, Dolznig H, Kollmann K, Vesely PW, Schlederer M, Merkel O, Schiefer A-I, Hassler MR, Heider S, Amenitsch L, Thallinger C, Staber PB, Simonitsch-Klupp I, Artaker M, Lagger S, Turner SD, Pileri S, Piccaluga PPaolo, 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 |
| Journal | Nat Med |
| Volume | 18 |
| Issue | 11 |
| Pagination | 1699-704 |
| Date Published | 2012 Nov |
| ISSN | 1546-170X |
| Keywords | Adult, Anaplastic Lymphoma Kinase, Animals, Benzamides, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Imatinib Mesylate, Lymphoma, Large-Cell, Anaplastic, Mice, Mice, Transgenic, Molecular Targeted Therapy, Neoplasm Staging, Nuclear Proteins, Oncogene Protein p65(gag-jun), Piperazines, Protein-Tyrosine Kinases, Pyrimidines, Receptor Protein-Tyrosine Kinases, Receptor, Platelet-Derived Growth Factor alpha, Receptor, Platelet-Derived Growth Factor beta, Remission Induction, Stem Cell Transplantation, Transcription Factor AP-1, Translocation, Genetic |
| 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. |
| DOI | 10.1038/nm.2966 |
| Alternate Journal | Nat Med |
| PubMed ID | 23064464 |
Related Faculty:
Giorgio Inghirami, M.D.