Abstract 3351: Aberrant RNA editing of GLI1 promotes malignant regeneration in multiple myeloma
Bibliographic record
Abstract
Abstract Introduction: Despite novel therapies, most of multiple myeloma (MM) patients relapse as a result of clonal evolution in inflammatory microenvironments. Adenosine-to-inosine (A-to-I) RNA editing, driven by inflammatory cytokine-responsive adenosine deaminase acting on RNA1 (ADAR1), promotes cancer progression by enhancing survival and self-renewal of malignant progenitor cells. Amplifications of chromosome 1q21, containing IL-6R and ADAR1 loci, occur frequently in high-risk MM patients, who frequently develop secondary plasma cell leukemia (PCL) and have shorter survival. While increased IL-6 signaling has been linked to relapse and A-to-I editing contributes to therapeutic resistance in a broad array of malignancies, the role of ADAR1 in MM pathogenesis has not been elucidated. This study aimed to investigate whether pro-inflammatory cues in MM activate ADAR1 editing thereby promoting malignant regeneration. Procedures: Publicly available primary patient datasets were analyzed and validated in a separate cohort of biobanked primary samples and human myeloma cell lines. Lentiviral vector-mediated activation or knockdown of ADAR1, or treatment with extrinsic pro-inflammatory stimuli, was utilized to probe the functional impact of RNA editing activity in MM models. Site-specific qPCR was used to quantify RNA editing in specific cancer stem cell-associated loci. Functional effects of ADAR1 activity were assessed in in vitro survival and self-renewal assays, and in novel in vivo PCL xenografts. Results: Patients harboring 1q21 amplification showed significant and stage-dependent increases in ADAR1 expression. In a set of separate primary PCL samples, aberrant RNA editing in the coding region of the Hedgehog (Hh) pathway transcription factor GLI1 was observed in high ADAR1-expressing samples. Notably, increased GLI1 editing, previously reported to have increased capacity to activate its transcriptional targets, was detected in serially transplantable, patient-derived xenograft models. Furthermore, abolition of ADAR1 editase activity impaired GLI1 editing. Lastly, in vitro pro-inflammatory IL-6 stimulation, or continuous exposure to the immunomodulatory drug lenalidomide led to increased ADAR1 mRNA and protein levels, with a concomitant induction of RNA editing activity. Conclusions: In MM, 1q21 amplification has been linked to progression. We provide new evidence linking expression and activity of ADAR1, located on 1q21, and disease stage. Because ADAR1 induces transcript recoding, A-to-I editing could contribute to the marked transcriptomic diversity typical of advanced MM. While the Hh pathway has been linked to cancer stem cell generation in human MM, here we identified a primate-specific mechanism of Hh pathway activation in MM through RNA editing-dependent stabilization of GLI1. Together, both genetic and microenvironmental factors modulate epitranscriptomic deregulation of cancer stem cell pathways in MM. Citation Format: Elisa Lazzari, Nathaniel Delos Santos, Christina Wu, Heather Leu, Gabriel Pineda, Shawn Ali, Caitlin Costello, Mark Minden, Raffaella Chiaramonte, Leslie Crews, Catriona Jamieson. Aberrant RNA editing of GLI1 promotes malignant regeneration in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3351. doi:10.1158/1538-7445.AM2017-3351
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".