PO-182 Examining the function of PDGFRB in anaplastic large cell lymphoma

Introduction Anaplastic large-cell lymphoma (ALCL) is an aggressive non-Hodgkin T-cell lymphoma (NHL) most commonly diagnosed in children and young adults. A majority of ALCL tumours harbour the translocation t( 2;5 (p23;q35), resulting in the fusion of Nucleophosmin ( NPM ) to the Anaplastic lymphoma kinase ( ALK ) gene. The oncogenic fusion protein (NPM-ALK) is constitutively expressed and consequently contributes to the pathogenesis and progression of about 70% of ALCL cases. Recent studies from our lab identified AP-1 transcription factors JUNB and cJUN as downstream effectors of NPM-ALK, which directly up-regulate platelet derived growth factor receptor beta (PDGFRB) expression in lymphoma cells. We demonstrated that besides increased receptor expression its ligand, PDGFB levels are also elevated in both mouse ALCL tumours and human ALCL patient plasma. Furthermore, therapeutic inhibition of PDGFRB with the kinase inhibitor imatinib resulted in rapid and sustained remission in late-stage therapy-resistant ALCL patients. Material and methods Despite these discoveries, the underlying mechanisms and the nature of PDGFRB signalling in lymphoma formation and progression still remain to be resolved. To elucidate the mechanisms of PDGFRB signalling in ALCL, we have crossed a murine ALCL model, which expresses NPM-ALK under the CD4 promoter, to PDGFRB floxed mice and a CD4 promoter driven Cre recombinase, to yield a specific deletion of PDGFRB in T cells ( CD4 -NPM-ALK-CD4 ΔPDGFRB ). Results and discussions Intriguingly, CD4 -NPM-ALK-CD4 ΔPDGFRB mice have significantly prolonged survival rates and reduced tumour growth, due to increased apoptosis. CD4 -NPM-ALK-CD4 ΔPDGFRB tumours exhibit a decrease in lymphatic vessels, which is accompanied by a decrease in tumour dissemination. Moreover, in vivo deletion of PDGFRB results in a decrease in the signal transducer and activator of transcription (STAT) and NPM-ALK signalling pathways dampening tumour aggressiveness. Manipulation of PDGFRB levels in vitro, via CRISPR/Cas9 mediated knockout or overexpression, in primary tumour cell lines isolated from CD4 -NPM-ALK-CD4 and CD4 -NPM-ALK-CD4 ΔPDGFRB mirrors the changes in signalling pathway observed in the tumours in vivo . Conclusion In summary, loss of PDGFRB leads to decreased tumour development and dissemination in a CD4- NPM-ALK mouse model via modulation of the STAT-signalling pathway. Our data therefore supports the oncogenic role of PDGFRB and opens new avenues for therapeutic intervention in ALCL treatment.