Abstract 2219: STAT3 network dissection in ALK positive Anaplastic Large Cell Lymphomas

Abstract

Abstract Anaplastic large cell lymphoma (ALCL) represents a category of T-cell Non-Hodgkin Lymphomas characterized by marked cellular pleomorphism, and expression of CD30. Two systemic forms of ALCL are defined by the presence or absence of chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene at 2p23 locus. Among several pathways triggered by ALK signaling, it has been widely shown that the constitutive activation of STAT3 is strictly required for ALK-mediated transformation and survival. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we performed gene and miRNA expression profiling experiments in association with functional validation approaches. The transcriptome of STAT3 was analysed in ALK positive ALCL cell lines using a tightly controlled time course experimental condition, in which the STAT3 signalling was abrogated by an inducible short hairpin RNA (shRNA). Gene expression profiling analysis identified a selected number of genes (1730) specifically modulated by STAT3 silencing. A significant overrepresentation of putative STAT3 binding sites was found in regulatory regions of early down-regulated genes. Functional studies using a shRNA lentiviral library established that Interferon Regulatory Factor-4 (IRF4) targeting specifically affect cell viability of ALK+ ALCL cells. In contrast, forced expression of IRF4 partially rescued STAT3 knock-down sustaining the survival of ALK+ cells. In a parallel experiment, genome-wide miRNA expression profiling identified 48 miRNAs concordantly modulated by the inducible knock down of ALK and STAT3. Among these, we demonstrated that expression of miR-17∼92 cluster significantly reverted STAT3 deprivation, sustaining both proliferation and survival of ALCL cells. In conclusion, genes and miRNA expression profiling associated to functional screenings allowed the identification of new biologically relevant targets for ALK+ALCL. We speculate that IRF4 and miR-17∼92 cluster are involved in the lymphomagenesis of STAT3+ ALCL, and that their inhibition might represent an alternative avenue to interfere with ALK signaling in Anaplastic Large Cell Lymphomas. Citation Format: Elisa Spaccarotella, Aldi Pupuleku, Elisa Pellegrino, Cecilia Bandini, Manuela Ferracin, Daniela Cantarella, Andrea Rinaldi, Paolo Provero, Ferdinando Di Cunto, Enzo Medico, Francesco Bertoni, Giorgio Inghirami, Roberto Piva. STAT3 network dissection in ALK positive Anaplastic Large Cell Lymphomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2014-2219