TY - JOUR
T1 - PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma
AU - Garces de Los Fayos Alonso, I
AU - Zujo, L
AU - Wiest, I
AU - Kodajova, P
AU - Timelthaler, G
AU - Edtmayer, S
AU - Zrimšek, M
AU - Kollmann, S
AU - Giordano, C
AU - Kothmayer, M
AU - Neubauer, H A
AU - Dey, S
AU - Schlederer, M
AU - Schmalzbauer, B S
AU - Limberger, T
AU - Probst, C
AU - Pusch, O
AU - Högler, S
AU - Tangermann, S
AU - Merkel, O
AU - Schiefer, A I
AU - Kornauth, C
AU - Prutsch, N
AU - Zimmerman, M
AU - Abraham, B
AU - Anagnostopoulos, J
AU - Quintanilla-Martinez, L
AU - Mathas, S
AU - Wolf, P
AU - Stoiber, D
AU - Staber, P B
AU - Egger, G
AU - Klapper, W
AU - Woessmann, W
AU - Look, T A
AU - Gunning, P
AU - Turner, S D
AU - Moriggl, R
AU - Lagger, S
AU - Kenner, L
N1 - Funding Information:
LK, SDT and IG were supported by funds from a European Union Horizon 2020 Marie Sklodowska-Curie Innovative Training Network grant, (ALKATRAS) award n. 675712. LK, SL, IG, SDT, GE, OM, WW, LQM, SM, and WK are members of the European Research Initiative for ALK-Related Malignancies ( www.erialcl.net ). LK was supported by the BM Fonds (n. 15142), the Margaretha Hehberger Stiftung (n. 15142), the COMET Competence Center CBmed - Center for Biomarker Research in Medicine (n. FA791A0906.FFG), the Christian-Doppler Lab for Applied Metabolomics, and by the Austrian Science Fund (grants FWF: P26011 and P29251). SL was a member of the VetMed University of Vienna Post-Doctoral program.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo.CONCLUSIONS: We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.
AB - BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo.CONCLUSIONS: We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.
UR - http://www.scopus.com/inward/record.url?scp=85137041648&partnerID=8YFLogxK
U2 - 10.1186/s12943-022-01640-7
DO - 10.1186/s12943-022-01640-7
M3 - Journal article
C2 - 36045346
SN - 1476-4598
VL - 21
SP - 172
JO - Molecular Cancer
JF - Molecular Cancer
IS - 1
M1 - 172
ER -