Abstract 5457: The relationship between ADAR1 and STAT3 and its relevance in multiple myeloma

Abstract

Abstract Multiple myeloma (MM), the second most common hematological cancer, is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Survival of MM cells is highly dependent on the bone marrow microenvironment, which is enriched with an array of growth factors secreted by the BM stromal cells. Amongst these growth factors, interleukin-6 (IL6) has been reported to be a major driver for MM disease progression. In line with the mechanism of action of IL6, MM cells are associated with constitutive activation of the oncogenic STAT3 signaling. ADAR1, an RNA editing enzyme, exists in two distinct isoforms, namely the P110 and P150. Aberrant ADAR1 expression and activity have been reported in various cancer types, however, this remains elusive in MM. Herein, we analyzed the publicly available myeloma patient datasets and identified that ADAR1 is overexpressed in MM and its expression level is closely associated with patients' overall survival. In vitro and in vivo assays revealed that ADAR1 can drive the growth and proliferation of MM cells, underlining its potential oncogenic effects in MM. Till date, much studies have reported the association of aberrant ADAR1 expression and its canonical functions of RNA editing, however, the knowledge on the upstream regulators of ADAR1 is still largely limited. To elucidate the cause of ADAR1 overexpression in MM, human myeloma cell lines were stimulated with IL6 at different time points. Besides potently activating the STAT3 signaling, IL6 stimulation also renders an increased expression of ADAR1 P150 isoform, at both the protein and mRNA level, with minimal effects seen on the P110 isoform, suggesting a transcriptional regulation of P150 by STAT3. Downstream validations with ChiP-qPCR and Luciferase Reporter Assay revealed that ADAR1 P150 is a direct target of STAT3 transcription factor. Specific STAT3 inhibition caused a downregulation of P150 and its oncogenic properties. Likewise, ectopic introduction of P150 rendered a more proliferative profile in the cells. Interestingly, we also observed that IL6-induced-ADAR1 expression could in turn mediate the activity of STAT3 signaling to enhance the oncogenic signaling within MM. Cells with high ADAR1 demonstrated a more rapid IL6-induced-STAT3 activation. In summary, we identified that ADAR1 overexpression is clinically relevant in MM and is driven by the hyperactivity of IL6-STAT3 signaling. Our data suggests that the P150 isoform, instead of the P110, is the more critical driver of MM disease aggressiveness in the patients with constitutively activated STAT3 pathway. The potential interplay between ADAR1 and STAT3 may represent a novel mechanism by which IL6 confers oncogenicity in MM. Citation Format: Phaik Ju Teoh, Tae Hoon Chung, Henry Yang, Polly Chen, Wee Joo Chng. The relationship between ADAR1 and STAT3 and its relevance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5457.