PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.
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.
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Daniela
D
Laimer
Helmut
H
Dolznig
Karoline
K
Kollmann
Paul W
PW
Vesely
Michaela
M
Schlederer
Olaf
O
Merkel
Ana-Iris
AI
Schiefer
Melanie R
MR
Hassler
Susi
S
Heider
Lena
L
Amenitsch
Christiane
C
Thallinger
Philipp B
PB
Staber
Ingrid
I
Simonitsch-Klupp
Matthias
M
Artaker
Sabine
S
Lagger
Suzanne D
SD
Turner
Stefano
S
Pileri
Pier Paolo
PP
Piccaluga
Peter
P
Valent
Katia
K
Messana
Indira
I
Landra
Thomas
T
Weichhart
Sylvia
S
Knapp
Medhat
M
Shehata
Maria
M
Todaro
Veronika
V
Sexl
Gerald
G
Höfler
Roberto
R
Piva
Enzo
E
Medico
Bruce A
BA
Ruggeri
Mangeng
M
Cheng
Robert
R
Eferl
Gerda
G
Egger
Josef M
JM
Penninger
Ulrich
U
Jaeger
Richard
R
Moriggl
Giorgio
G
Inghirami
Lukas
L
Kenner
D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D016759:Oncogene Protein p65(gag-jun) / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012074:Remission Induction; D033581:Stem Cell Transplantation; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic
D001549:Benzamides; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016759:Oncogene Protein p65(gag-jun); D010879:Piperazines; D011743:Pyrimidines; D018808:Transcription Factor AP-1; D000090243:Nucleophosmin; D000068877:Imatinib Mesylate; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta