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.

Dental Pulp Stem Cell-Derived Exosomes Regulate Anti-Inflammatory and Osteogenesis in Periodontal Ligament Stem Cells and Promote the Repair of Experimental Periodontitis in Rats

“…In addition to the classical and simple signal transduction of the receptor-JAK-STAT- downstream pathway, the activation of some receptor tyrosine kinases (RTKs) can phosphorylate STAT through Src kinase, including epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR). 61 , 62 It can also activate mitogen-activated protein kinase (MAPK) through activation of the RTK/Ras pathway. MAPK can specifically phosphorylate the serine site (Ser727) at the C-terminus of STAT to enhance the transcriptional activity of STAT.…”

PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility

“…Lineage transition from Adeno to NEPC is relatively a common type of cancer cell plasticity in ADT-treated PCa [ 9 ]. It has been reported that STAT5A has a tightly correlation with lineage plasticity both in stem cells [ 56 ] and in tumors [ 57 , 58 ]. Therefore, we wondered whether PAX6 could promote NE trans-differentiation via STAT5A mediated changes of cells lineage plasticity.…”

Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia

“…This is supported by the fact that activating STAT5B mutations and particularly STAT5B N642H also occur in T cell large granular lymphocytic leukemia, T cell prolymphocytic leukemia, and various γδ T cell–derived leukemias/lymphomas ( 18 ). Furthermore, STAT5 activation is targetable in cutaneous T cell lymphomas, bearing STAT5A and STAT5B copy number gains, and PDGFRβ-driven anaplastic large cell lymphoma ( 55 , 60 ). STAT5 activating kinase triggers might lead to similar molecular consequences as STAT5B N642H , highlighting broad applicability of our results.…”