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.

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

PIVA, Roberto;MEDICO, Enzo;INGHIRAMI, Giorgio;
2012-01-01

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.
2012
Inglese
Esperti anonimi
18
11
1699
1705
7
STATI UNITI D'AMERICA
AUSTRIA
1 – prodotto con file in versione Open Access (allegherò il file al passo 6 - Carica)
262
38
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;Ar...espandi
info:eu-repo/semantics/article
open
03-CONTRIBUTO IN RIVISTA::03A-Articolo su Rivista
File in questo prodotto:
File Dimensione Formato  
2012-Identification of PDGFR_postprint_4aperto.pdf

Open Access dal 01/06/2013

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 1.14 MB
Formato Adobe PDF
1.14 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/126434
Citazioni
  • ???jsp.display-item.citation.pmc??? 57
  • Scopus 108
  • ???jsp.display-item.citation.isi??? 101
social impact