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

I Garces de Los Fayos Alonso; L Zujo; I Wiest; P Kodajova; G Timelthaler; S Edtmayer; M Zrimšek; S Kollmann; C Giordano; M Kothmayer; H A Neubauer; S Dey; M Schlederer; B S Schmalzbauer; T Limberger; C Probst; O Pusch; S Högler; 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; S D Turner; R Moriggl; S Lagger; L Kenner

doi:10.1186/s12943-022-01640-7

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

I Garces de Los Fayos Alonso, L Zujo, I Wiest, P Kodajova, G Timelthaler, S Edtmayer, M Zrimšek, S Kollmann, C Giordano, M Kothmayer, H A Neubauer, S Dey, M Schlederer, B S Schmalzbauer, T Limberger, C Probst, O Pusch, S Högler, S Tangermann, O MerkelA 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, S D Turner, R Moriggl, S Lagger, L Kenner

Division of Pharmacology

Research output: Journal article (peer-reviewed) › Journal article

12 Citations (Scopus)

Abstract

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.

Original language	English
Article number	172
Pages (from-to)	172
Number of pages	1
Journal	Molecular Cancer
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s12943-022-01640-7
Publication status	Published - Dec 2022

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Garces de Los Fayos Alonso, I., Zujo, L., Wiest, I., Kodajova, P., Timelthaler, G., Edtmayer, S., Zrimšek, M., Kollmann, S., Giordano, C., Kothmayer, M., Neubauer, H. A., Dey, S., Schlederer, M., Schmalzbauer, B. S., Limberger, T., Probst, C., Pusch, O., Högler, S., Tangermann, S., ... Kenner, L. (2022). PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma. Molecular Cancer, 21(1), 172. Article 172. https://doi.org/10.1186/s12943-022-01640-7

@article{b13c967c8e874da8aac649e9eb90f8c8,

title = "PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma",

abstract = "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.",

author = "{Garces de Los Fayos Alonso}, I and L Zujo and I Wiest and P Kodajova and G Timelthaler and S Edtmayer and M Zrim{\v s}ek and S Kollmann and C Giordano and M Kothmayer and Neubauer, {H A} and S Dey and M Schlederer and Schmalzbauer, {B S} and T Limberger and C Probst and O Pusch and S H{\"o}gler and S Tangermann and O Merkel and Schiefer, {A I} and C Kornauth and N Prutsch and M Zimmerman and B Abraham and J Anagnostopoulos and L Quintanilla-Martinez and S Mathas and P Wolf and D Stoiber and Staber, {P B} and G Egger and W Klapper and W Woessmann and Look, {T A} and P Gunning and Turner, {S D} and R Moriggl and S Lagger and L Kenner",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s12943-022-01640-7",

language = "English",

volume = "21",

pages = "172",

journal = "Molecular Cancer",

issn = "1476-4598",

publisher = "BioMed Central Ltd.",

number = "1",

}

Garces de Los Fayos Alonso, I, Zujo, L, Wiest, I, Kodajova, P, Timelthaler, G, Edtmayer, S, Zrimšek, M, Kollmann, S, Giordano, C, Kothmayer, M, Neubauer, HA, Dey, S, Schlederer, M, Schmalzbauer, BS, Limberger, T, Probst, C, Pusch, O, Högler, S, Tangermann, S, Merkel, O, Schiefer, AI, Kornauth, C, Prutsch, N, Zimmerman, M, Abraham, B, Anagnostopoulos, J, Quintanilla-Martinez, L, Mathas, S, Wolf, P, Stoiber, D, Staber, PB, Egger, G, Klapper, W, Woessmann, W, Look, TA, Gunning, P, Turner, SD, Moriggl, R, Lagger, S & Kenner, L 2022, 'PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma', Molecular Cancer, vol. 21, no. 1, 172, pp. 172. https://doi.org/10.1186/s12943-022-01640-7

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

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 -

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

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