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Plasma Cell Disorders
IL6R-STAT3-ADAR1 (P150) interplay promotes oncogenicity in multiple myeloma with 1q21 amplification
Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1391-1404
   Phaik Ju Teoh,1,2 Tae-Hoon Chung,1 Pamela Y.Z. Chng,1 Sabrina H. M. Toh1 and Wee Joo Chng1,2,3
1Cancer Science Institute of Singapore, National University of Singapore; 2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and 3Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore
  ABSTRACT
1q21 amplification is an important prognostic marker in multiple myelo- ma. In this study we identified that IL6R (the interleukin-6 membrane receptor) and ADAR1 (an RNA editing enzyme) are critical genes locat- ed within the minimally amplified 1q21 region. Loss of individual genes caused suppression to the oncogenic phenotypes, the magnitude of which was enhanced when both genes were concomitantly lost. Mechanistically, IL6R and ADAR1 collaborated to induce a hyper-activation of the oncogenic STAT3 pathway. High IL6R confers hypersensitivity to interleukin-6 bind- ing, whereas, ADAR1 forms a constitutive feed-forward loop with STAT3 in a P150-isoform-predominant manner. In this respect, ADAR1-P150 acts as a direct transcriptional target for STAT3 and this STAT3-induced-P150 in turn directly interacts with and stabilizes the former protein, leading to a larger pool of proteins acting as oncogenic transcription factors for pro-survival genes. The importance of both IL6R and ADAR1-P150 in STAT3 signaling was further validated when concomitant knockdown of both genes imped- ed IL6-induced-STAT3 pathway activation. Clinical evaluation of various datasets of myeloma patients showed that low expression of either one or both genes was closely associated with a compromised STAT3 signature, confirming the involvement of IL6R and ADAR1 in the STAT3 pathway and underscoring their essential role in disease pathogenesis. In summary, our findings highlight the complexity of the STAT3 pathway in myeloma, in association with 1q21 amplification. This study therefore reveals a novel perspective on 1q21 abnormalities in myeloma and a potential therapeutic target for this cohort of high-risk patients.
Introduction
Multiple myeloma (MM) is a latent type of hematologic malignancy character- ized by abnormal accumulation of plasma cells in the bone marrow. It is well estab- lished that MM cells are highly dependent on the bone marrow microenvironment enriched with growth factors for support and propagation.1-3 Among these factors, interleukin-6 (IL6), which is secreted in an autocrine and paracrine fashion, is piv- otal for the survival and proliferation of MM cells: high expression of IL6 prevents drug-induced-apoptosis.1,4-6 Blood serum from MM patients contains elevated levels of IL6 and this is significantly associated with worse disease outcome.6,7
Mechanistically, IL6 confers oncogenicity through the activation of the Janus kinases (JAK)/signal transducers and activators of transcription 3 (STAT3) pathway, initiated with its binding to the transmembrane receptor IL6R.4,8,9 STAT3 is activat- ed when its tyrosine-705 (Y705) is phosphorylated by JAK upon IL6 stimulation, leading to transcription of various pro-survival and anti-apoptotic genes such as MCL1 and BCL2.10,11 In line with this mechanism of action, primary MM tumors possess constitutive activation of the STAT3 pathway (incidence rate of 40-60%) with close correlation with poor prognosis and chemoresistance,9,12-14 suggesting that IL6/STAT3 signaling is essential for MM therapeutic targeting.
   Correspondence:
WEE JOO CHNG
csicwj@nus.edu.sg
Received: March 6, 2019. Accepted: August 12, 2019. Pre-published: August 14, 2019.
doi:10.3324/haematol.2019.221176
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1391
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