PDGFR[beta] promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma
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 e...
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Published in | Molecular cancer Vol. 21; no. 1 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
BioMed Central Ltd
31.08.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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.sub.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.sup.+ ALCL patients. Keywords: ALCL, PDGFR[beta], STAT3, STAT5A, STAT5B, NPM-ALK, Apoptosis |
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ISSN: | 1476-4598 1476-4598 |
DOI: | 10.1186/s12943-022-01640-7 |