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Cited by 60Multiple Myeloma Research and TreatmentsCytokine Signaling Pathways and InteractionsRNA regulation and disease

IL6R-STAT3-ADAR1 (P150) interplay promotes oncogenicity in multiple myeloma with 1q21 amplification

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Teoh, Phaik Ju, Chung, Tae-Hoon, Chng, Pamela Y.Z., Toh, Sabrina H. M., Chng, Wee Joo·2020·Haematologica
DOI 10.3324/haematol.2019.221176PMC PMC7193471
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Abstract

1q21 amplification is an important prognostic marker in multiple myeloma. In this study we identified that IL6R (the interleukin-6 membrane receptor) and ADAR1 (an RNA editing enzyme) are critical genes located 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 binding, 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 impeded 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.

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  • IL-6R evokes a myriad of responses, including metabolic actions, through STAT3.

    “IL-6R evokes a myriad of responses, including metabolic actions, through STAT3.31,32,33,34”

    From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [34]

    The Introduction (page not provided) describes IL-6 binding to IL6R and activating STAT3, while the Discussion reports resulting growth and proliferation in myeloma cells. Neither passage identifies metabolic actions as one of the responses, so that part of the claim is unsupported by our copy. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Teoh, P. J., Chung, T.-H., Chng, P. Y. Z., Toh, S. H. M., & Chng, W. J.
Affiliations
National University of Singapore (SG)
Corresponding author
Chng, Wee Joo
ORCID
Venue
Haematologica
Publisher
Ferrata Storti Foundation (Haematologica)
Published
2019-08-14
Volume
105
Issue
5
Pages
1391-1404
ISSN
  • 0390-6078 (ISSN-L)
  • 1592-8721
DOI
10.3324/haematol.2019.221176
PMC
PMC7193471
OpenAlex
W2968345818
Cited by
60
References
1
Citations by year
2026: 3 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 13 · 2021: 11 · 2020: 3 · 2012: 1
FWCI
4.77
Type
journal article
Language
en
Open access
Locations
  • Haematologica (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Research Foundation
  • National Research Foundation Singapore (MOE2014-T3-1-006)
  • Ministry of Education, India
  • National Medical Research Council (MOE2014-T3-1-006)
  • Cancer Science Institute of Singapore, National University of Singapore (MOE2014-T3-1-006)
  • National Supercomputing Center, Korea Institute of Science and Technology Information
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
multiple myeloma, 1q21 amplification, IL-6 receptor, ADAR1, STAT3 signaling, RNA editing, feed-forward loop, protein stability, interleukin-6, oncogenicity, transcriptional regulation, prognostic factors, therapeutic target
MeSH terms
Adenosine Deaminase, Humans, Multiple Myeloma, RNA-Binding Proteins, RNA Editing, Receptors, Interleukin-6, Protein Isoforms, STAT3 Transcription Factor

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