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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F22%3A00128531" target="_blank" >RIV/00216224:14740/22:00128531 - isvavai.cz</a>

Výsledek na webu

<a href="https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01640-7" target="_blank" >https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01640-7</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s12943-022-01640-7" target="_blank" >10.1186/s12943-022-01640-7</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecular Cancer

ISSN

1476-4598

e-ISSN

—

Svazek periodika

21

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

119

Strana od-do

172

Kód UT WoS článku

000849356900001

EID výsledku v databázi Scopus

2-s2.0-85137041648