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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Anaplastic Lymphoma Kinase
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Animals
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Benzamides
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Imatinib Mesylate
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Lymphoma, Large-Cell, Anaplastic* / drug therapy
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Lymphoma, Large-Cell, Anaplastic* / metabolism
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Lymphoma, Large-Cell, Anaplastic* / pathology
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Mice
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Mice, Transgenic
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Molecular Targeted Therapy
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Neoplasm Staging
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Nuclear Proteins* / genetics
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Nuclear Proteins* / metabolism
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Nucleophosmin
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Oncogene Protein p65(gag-jun) / genetics
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Oncogene Protein p65(gag-jun) / metabolism
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Piperazines / administration & dosage
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Protein-Tyrosine Kinases* / genetics
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Protein-Tyrosine Kinases* / metabolism
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Pyrimidines / administration & dosage
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Receptor Protein-Tyrosine Kinases* / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases* / genetics
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Receptor Protein-Tyrosine Kinases* / metabolism
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Receptor, Platelet-Derived Growth Factor alpha* / antagonists & inhibitors
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Receptor, Platelet-Derived Growth Factor alpha* / genetics
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Receptor, Platelet-Derived Growth Factor alpha* / metabolism
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Receptor, Platelet-Derived Growth Factor beta* / antagonists & inhibitors
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Receptor, Platelet-Derived Growth Factor beta* / genetics
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Receptor, Platelet-Derived Growth Factor beta* / metabolism
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Remission Induction
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Stem Cell Transplantation
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Translocation, Genetic
Substances
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Benzamides
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NPM1 protein, human
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Nuclear Proteins
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Oncogene Protein p65(gag-jun)
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Piperazines
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Pyrimidines
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Transcription Factor AP-1
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Nucleophosmin
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Imatinib Mesylate
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p80(NPM-ALK) protein
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
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Receptor, Platelet-Derived Growth Factor alpha
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Receptor, Platelet-Derived Growth Factor beta