Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm.
Fiche publication
Date publication
août 2017
Journal
Haematologica
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DECONINCK Eric, Pr GARNACHE-OTTOU Francine, Dr ANGELOT-DELETTRE Fanny
Tous les auteurs :
Philippe L, Ceroi A, Bôle-Richard E, Jenvrin A, Biichle S, Perrin S, Limat S, Bonnefoy F, Deconinck E, Saas P, Garnache-Ottou F, Angelot-Delettre F
Lien Pubmed
Résumé
Blastic plasmacytoid dendritic cell neoplasm is an aggressive hematological malignancy with a poor prognosis. No consensus for optimal treatment modalities is available today. Targeting the NF-κB pathway is considered as a promising approach since blastic plasmacytoid dendritic cell neoplasm have been reported to exhibit a constitutive activation of the NF-κB pathway. Moreover, NF-κB inhibition in blastic plasmacytoid dendritic cell neoplasm cell lines using either an experimental specific inhibitor JSH23 or the clinical drug bortezomib interferes in vitro with leukemic cell proliferation and survival. We extended here these data by showing that primary blastic plasmacytoid dendritic cell neoplasm cells from 7 patients were sensitive to bortezomib-induced cell death. We confirmed that bortezomib inhibits efficiently the phosphorylation of the RelA NF-κB subunit in blastic plasmacytoid dendritic cell neoplasm cell lines and primary cells from patients in vitro and in vivo in a mouse model. Then, we demonstrated that bortezomib can be associated with other drugs used in different chemotherapy regimens to improve its impact on leukemic cell death. Indeed, when primary blastic plasmacytoid dendritic cell neoplasm cells from a patient were grafted, bortezomib treatment significantly increased mouse survival, and was associated with a significant decrease of circulating leukemic cells and RelA NF-κB subunit expression. Overall, our results provide a rationale for the use of bortezomib in combination with other chemotherapy for the treatment of blastic plasmacytoid dendritic cell neoplasm patients. Based on our data, a prospective clinical trial combining proteasome inhibitor with classical drugs could be envisaged.
Mots clés
Animals, Antineoplastic Agents, pharmacology, Bortezomib, pharmacology, Cell Cycle, genetics, Cell Line, Tumor, Cell Proliferation, drug effects, Dendritic Cells, metabolism, Disease Models, Animal, Humans, Leukemia, Myeloid, Acute, drug therapy, Mice, NF-kappa B, metabolism, Signal Transduction, drug effects, Xenograft Model Antitumor Assays
Référence
Haematologica. 2017 Aug;: