Abstract LB-392: JunB and cJun dependent PDGFRβ expression reveals imatinib/nilotinib treatment as effective therapeutic strategy for ALK driven lymphomas.

Abstract

Abstract Anaplastic large cell lymphomas (ALCLs) are frequent non Hodgkin Lymphomas of T-cell origin, comprising 40% of all non-Hodgkin Lymphomas of childhood and 2–8% of adulthood. Half of the cases are associated with a t(2;5) translocation, leading to the fusion of NPM gene and ALK tyrosine kinase, resulting in its constitutive activation. The AP-1 transcription factors JunB and cJun are downstream effectors of NPM-ALK. To investigate the role of JunB and cJun in NPM-ALK mediated tumorgenesis, we used a murine NPM-ALK T- cell lymphoma model in which the conditional deletion of JunB and cJun was selectively restricted to CD4+ T lymphocytes. Loss of JunB and cJun in transgenic T cells resulted in significantly increased disease latency and doubled the mean survival rate. We identified PDGFRβ as direct target of cJun and JunB. These transcription factors directly bind to a highly conserved AP-1 site within the promoter region of PDGFRβ and activate its transcription in vitro. We further investigated the effects of PDGFRβ inhibition in NPM-ALK xenografts and in a murine NPM-ALK T-cell lymphoma model using the kinase inhibitors imatinib and nilotinib. Treated xenografts showed significant smaller tumor masses, CD4-NPM-ALK mice displayed a drastic increase in mean survival rate. Based on these very promising data we even had the chance to check effects of imatinib therapy in a patient with relapsed ALK+ ALCL. After treatment with six cycles CHOP, one cycle ICE, allogenic stem cell transplantation with previous conditioning with BEAM, he received imatinib. Within one week of therapy lymph nodes regressed and B-symptoms declined. A PET-CT revealed complete remission two weeks after imatinib initiation. In summary, these data demonstrate a pathogenic role of JunB/cJun as well as PDGFRβ in NPM-ALK mediated lymphomagenesis. Our study encourages the development of specific clinical trials for human ALCLs using tyrosine kinase inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-392. doi:10.1158/1538-7445.AM2011-LB-392