Activation of PDGFR drives NPM–ALK-positive anaplastic large-cell lymphoma (ALCL).
Major finding: Activation of PDGFR drives NPM–ALK-positive anaplastic large-cell lymphoma (ALCL).
Clinical relevance: Imatinib induced complete remission in a patient with refractory relapsed ALCL.
Impact: PDGFR inhibition is effective in ALCL and may be combined with ALK inhibition to prevent relapse.
Anaplastic large-cell lymphoma (ALCL) is an aggressive T-cell lymphoma that frequently harbors a chromosomal translocation resulting in expression of the nucleophosmin–anaplastic lymphoma kinase (NPM–ALK) oncoprotein. NPM–ALK has been implicated in the activation of the transcription factors JUN and JUNB, but it is unclear whether induction of these proteins contributes to NPM–ALK-driven cancers. Laimer and colleagues conditionally deleted Jun and/or Junb in the T-cells of mice expressing human NPM-ALK and found that deletion of both genes significantly prolonged the survival of NPM–ALK+ mice. Although lymphomas eventually formed, dissemination of tumor cells did not occur. Interestingly, lymphomas of NPM–ALK+, Jun/Junb–deficient mice had low numbers of blood vessels associated with reduced levels of the pericyte marker platelet-derived growth factor receptor-β (PDGFRB). Chromatin immunoprecipitation and luciferase reporter assays in human cells showed that JUN and JUNB transcriptionally activate PDGFRB, suggesting that PDGFRB might represent a therapeutic target in NPM–ALK+ ALCL. Indeed, inhibition of PDGFRB with imatinib suppressed the proliferation of transplanted and primary NPM–ALK+ ALCL tumor cells and prolonged overall survival in mice. Additionally, imatinib treatment led to regression of established NPM–ALK+ lymphomas and prevented relapse after treatment with the ALK inhibitor crizotinib. Expression of JUN, JUNB, PDGFRA, and PDGFRB was specifically elevated in human ALCL compared with other lymphomas, suggesting that these findings may be clinically relevant. Imatinib treatment in a patient whose ALCL was positive for NPM-ALK, JUN, JUNB, PDGFRA, and PDGFRB led to a complete remission within 10 days that was ongoing almost 2 years later. This study thus identifies PDGFR as a therapeutic target in relapsed or refractory ALCL and suggests that combined inhibition of PDGFR and ALK may reduce recurrence rates in this disease.