PDGFR beta promotes oncogenic progression via STAT3/STAT5
hyperactivation in anaplastic large cell lymphoma

J 2022

PDGFR beta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma

ALONSO, I Garces de los Fayos, L. ZUJO, I. WIEST, P. KODAJOVA, G. TIMELTHALER et. al.

Basic information

Original name

PDGFR beta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma

Authors

ALONSO, I Garces de los Fayos, L. ZUJO, I. WIEST, P. KODAJOVA, G. TIMELTHALER, S. EDTMAYER, M. ZRIMSEK, S. KOLLMANN, C. GIORDANO, M. KOTHMAYER, H A. NEUBAUER, S. DEY, M. SCHLEDERER, B S. SCHMALZBAUER, T. LIMBERGER, C. PROBST, O. PUSCH, S. HOGLER, S. TANGERMANN, O. MERKEL, A I. SCHIEFER, C. KORNAUTH, N. PRUTSCH, M. ZIMMERMAN, B. ABRAHAM, J. ANAGNOSTOPOULOS, L. QUINTANILLA-MARTINEZ, S. MATHAS, P. WOLF, D. STOIBER, P B. STABER, G. EGGER, W. KLAPPER, W. WOESSMANN, T A. LOOK, P. GUNNING, Suzanne Dawn TURNER (826 United Kingdom of Great Britain and Northern Ireland, guarantor, belonging to the institution), R. MORIGGL, S. LAGGER and L. KENNER

Edition

Molecular Cancer, BioMed Central Ltd, 2022, 1476-4598

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 37.300

RIV identification code

RIV/00216224:14740/22:00128531

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1186/s12943-022-01640-7

UT WoS

000849356900001

Keywords in English

ALCL; PDGFR beta; STAT3; STAT5A; STAT5B; NPM-ALK; Apoptosis

Abstract

V originále

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 PDGFR beta. Blocking PDGFR beta 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 PDGFR beta-driven human ALCL in vivo, we identify PDGFR beta as a driver of aggressive tumor growth. Mechanistically, PDGFR beta induces the pro-survival factor Bcl-x(L) 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 PDGFR beta as a novel biomarker and introduce PDGFR beta-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFR beta or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK(+) ALCL patients.

Citovat

ALONSO, I Garces de los Fayos, L. ZUJO, I. WIEST, P. KODAJOVA, G. TIMELTHALER, S. EDTMAYER, M. ZRIMSEK, S. KOLLMANN, C. GIORDANO, M. KOTHMAYER, H A. NEUBAUER, S. DEY, M. SCHLEDERER, B S. SCHMALZBAUER, T. LIMBERGER, C. PROBST, O. PUSCH, S. HOGLER, S. TANGERMANN, O. MERKEL, A I. SCHIEFER, C. KORNAUTH, N. PRUTSCH, M. ZIMMERMAN, B. ABRAHAM, J. ANAGNOSTOPOULOS, L. QUINTANILLA-MARTINEZ, S. MATHAS, P. WOLF, D. STOIBER, P B. STABER, G. EGGER, W. KLAPPER, W. WOESSMANN, T A. LOOK, P. GUNNING, Suzanne Dawn TURNER, R. MORIGGL, S. LAGGER and L. KENNER. PDGFR beta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma. Molecular Cancer. BioMed Central Ltd, 2022, vol. 21, No 1, p. 172, 1-19. ISSN 1476-4598. Available from: https://dx.doi.org/10.1186/s12943-022-01640-7.

@article{2252418,
   author = {Alonso, I Garces de los Fayos and Zujo, L. and Wiest, I. and Kodajova, P. and Timelthaler, G. and Edtmayer, S. and Zrimsek, M. and Kollmann, S. and Giordano, C. and Kothmayer, M. and Neubauer, H A. and Dey, S. and Schlederer, M. and Schmalzbauer, B S. and Limberger, T. and Probst, C. and Pusch, O. and Hogler, S. and Tangermann, S. and Merkel, O. and Schiefer, A I. and Kornauth, C. and Prutsch, N. and Zimmerman, M. and Abraham, B. and Anagnostopoulos, J. and QuintanillaandMartinez, L. and Mathas, S. and Wolf, P. and Stoiber, D. and Staber, P B. and Egger, G. and Klapper, W. and Woessmann, W. and Look, T A. and Gunning, P. and Turner, Suzanne Dawn and Moriggl, R. and Lagger, S. and Kenner, L.},
   article_number = {1},
   doi = {http://dx.doi.org/10.1186/s12943-022-01640-7},
   keywords = {ALCL; PDGFR beta; STAT3; STAT5A; STAT5B; NPM-ALK; Apoptosis},
   language = {eng},
   issn = {1476-4598},
   journal = {Molecular Cancer},
   title = {PDGFR beta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma},
   url = {https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01640-7},
   volume = {21},
   year = {2022}
}

TY  - JOUR
ID  - 2252418
AU  - Alonso, I Garces de los Fayos - Zujo, L. - Wiest, I. - Kodajova, P. - Timelthaler, G. - Edtmayer, S. - Zrimsek, M. - Kollmann, S. - Giordano, C. - Kothmayer, M. - Neubauer, H A. - Dey, S. - Schlederer, M. - Schmalzbauer, B S. - Limberger, T. - Probst, C. - Pusch, O. - Hogler, S. - Tangermann, S. - Merkel, O. - Schiefer, A I. - Kornauth, C. - Prutsch, N. - Zimmerman, M. - Abraham, B. - Anagnostopoulos, J. - Quintanilla-Martinez, L. - Mathas, S. - Wolf, P. - Stoiber, D. - Staber, P B. - Egger, G. - Klapper, W. - Woessmann, W. - Look, T A. - Gunning, P. - Turner, Suzanne Dawn - Moriggl, R. - Lagger, S. - Kenner, L.
PY  - 2022
TI  - PDGFR beta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma
JF  - Molecular Cancer
VL  - 21
IS  - 1
SP  - 172
EP  - 172
PB  - BioMed Central Ltd
SN  - 14764598
KW  - ALCL
KW  - PDGFR beta
KW  - STAT3
KW  - STAT5A
KW  - STAT5B
KW  - NPM-ALK
KW  - Apoptosis
UR  - https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01640-7
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 PDGFR beta. Blocking PDGFR beta 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 PDGFR beta-driven human ALCL in vivo, we identify PDGFR beta as a driver of aggressive tumor growth. Mechanistically, PDGFR beta induces the pro-survival factor Bcl-x(L) 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 PDGFR beta as a novel biomarker and introduce PDGFR beta-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFR beta or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK(+) ALCL patients.
ER  -

ALONSO, I Garces de los Fayos, L. ZUJO, I. WIEST, P. KODAJOVA, G. TIMELTHALER, S. EDTMAYER, M. ZRIMSEK, S. KOLLMANN, C. GIORDANO, M. KOTHMAYER, H A. NEUBAUER, S. DEY, M. SCHLEDERER, B S. SCHMALZBAUER, T. LIMBERGER, C. PROBST, O. PUSCH, S. HOGLER, S. TANGERMANN, O. MERKEL, A I. SCHIEFER, C. KORNAUTH, N. PRUTSCH, M. ZIMMERMAN, B. ABRAHAM, J. ANAGNOSTOPOULOS, L. QUINTANILLA-MARTINEZ, S. MATHAS, P. WOLF, D. STOIBER, P B. STABER, G. EGGER, W. KLAPPER, W. WOESSMANN, T A. LOOK, P. GUNNING, Suzanne Dawn TURNER, R. MORIGGL, S. LAGGER and L. KENNER. PDGFR beta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma. \textit{Molecular Cancer}. BioMed Central Ltd, 2022, vol.~21, No~1, p.~172, 1-19. ISSN~1476-4598. Available from: https://dx.doi.org/10.1186/s12943-022-01640-7.

Detailed Information on Publication Record