Citations 2
Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study
Ou, Anna , Adli, Mazda , Akiyama, Kazufumi , Akula, Nirmala , Amare, Azmeraw T. , Ardau, Raffaella , Arias, Bárbara , Aubry, Jean‐Michel , Bauer, Michael , Benabarre, Antonio , Bengesser, Susanne , Abesh, Bhattacharjee, Bui, Elise T. , Cervantes, Pablo , Chillotti, Caterina , Cichon, Sven , Clark, Scott R. , Cousins, David A. , Cruceanu, Cristiana , Degenhardt, Franziska , Ferensztajn‐Rochowiak, Ewa , Forstner, Andreas J. , Frisén, Louise , Frye, Mark A. , Gard, Sébastien, Grof, Paul , Gruber, Oliver , Kahn, Jean‐Pierre, Kassem, Layla, Kittel‐Schneider, Sarah , Dalkner, Nina , Laje, Gonzalo, Landén, Mikael , Lavebratt, Catharina , Leckband, Susan G. , López‐Jaramillo, Carlos , Maj, Mario , Mattheisen, Manuel , McCarthy, Michael J. , Mitjans, Marina , Mondimore, Francis M. , Nöthen, Markus M. , Ösby, Urban, Perlis, Roy H. , Pfennig, Andrea , Potash, James B. , Schalling, Martin , Schubert, Klaus Oliver , Schweizer, Barbara , Severino, Giovanni , Shekhtman, Tatyana , Shilling, Paul D. , Shimoda, Kazutaka , Simhandl, Christian , Slaney, Claire , Stamm, Thomas , Tighe, Sarah K., Volkert, Julia, Witt, Stephanie H. , Zandi, Peter P. , Zompo, Maria Del , Ou, Anna , Alda, Martin , Amare, Azmeraw , Arias, Bárbara , Bauer, M , Baune, Bernhard , Biernacka, Joanna , Chen, Hsi-Chung , Clark, Scott , Cruceanu, Cristiana , Czerski, Piotr , DePaulo, J Raymond , Etain, B , Forstner, Andreas J , Frye, Mark , Fullerton, Janice M , Garnham, Julie , Grigoroiu-Serbanescu, Maria , Hashimoto, Ryota , Hauser, Joanna , Heilbronner, Urs , Hou, Liping , Jamain, Stéphane , Kato, Tadafumi , Kuo, Po-Hsiu , Kusumi, Ichiro , Landén, Mikael , Lavebratt, Catharina , Leboyer, Marion , Marie-Claire, Cynthia , McMahon, Francis , Mitchell, Philip B , Mitjans, Marina , Nievergelt, Caroline M , Nöthen, Markus M , Novak, Tomas , Ozaki, Norio , Papiol, Sergi , Reif, Andreas , Reininghaus, Eva , Rietschel, Marcella , Rouleau, Guy Armand , Rybakowski, Janusz K , Schalling, Martin , Schofield, Peter R , Schubert, Klaus Oliver , Schulze, Thomas , Severino, Giovanni , Shilling, Paul , Shimoda, Kazutaka , Squassina, Alessio , Turecki, Gustavo , Vieta, E , Witt, Stephanie H , Wray, Naomi , Del Zompo, Maria , Cichon, Sven , López-Jaramillo, Carlos , Kittel-Schneider, Sarah , McCarthy, Michael , Perlis, Roy H , Kelsoe, John R , Jiang, Qingfei , Alda, Martin , Backlund, Lena , Banzato, Cláudio E. M. , Bellivier, Frank , Biernacka, Joanna M. , Chen, Guo‐Bo , Chen, Hsi‐Chung , Colom, Francesc , Czerski, Piotr M. , Dantas, Clarissa de Rosalmeida , Dayer, Alexandre G. , Étain, Bruno , Falkai, Peter , Fellendorf, Frederike T. , Fullerton, Janice M. , Goes, Fernando , Grigoroiu‐Serbânescu, Maria , Hashimoto, Ryota , Heilbronner, Urs , Herms, Stefan , Hoffmann, Per , Hofmann, Andrea , Jamain, Stéphane , Jiménez, Esther , Kato, Tadafumi , König, Barbara , Kuo, Po‐Hsiu , Dalkner, Nina , Leboyer, Marion , MacQUEEN, GLENDA M. , Manchia, Mirko , Martinsson, Lina , McElroy, Susan L. , McMahon, Francis J. , Monteleone, Palmiero , Novák, Tomáš , Ozaki, Norio , Papiol, Sergi , Reich‐Erkelenz, Daniela , Reif, Andreas , Schofield, Peter R. , Seemüller, Florian , Squassina, Alessio , Stopková, Pavla , Tortorella, Alfonso , Turecki, Gustavo , Vieta, Eduard , Wright, Adam, Young, Trevor
No container title available | October 3, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
Abstract 4437: Down-modulation of ADAR1-mediated GLI1 editing alters extracellular and immune response genes in multiple myeloma
Mondala, Phoebe , Santos, Nathaniel P. Delos , Pineda, Gabriel, Costello, Caitlin , Minden, Mark D. , Stewart, A. Keith, Jamieson, Catriona , Crews, Leslie A. , Lazzari, Elisa , Miller, Amber , Jiang, Qingfei , Ganesan, Anusha-Preethi , Wu, Christina N. , Chiaramonte, Raffaella
Cancer Research | August 17, 2018 | Volume: 78 | Issue: 13_Supplement | Pages: 4437-4437
Abstract Introduction: Representing 10% of hematologic malignancies, multiple myeloma (MM) is typified by clonal plasma cell proliferation in the bone marrow (BM) and may progress to therapy-resistant plasma cell leukemia (PCL). Despite many novel therapies, relapse rates remain high as a result of malignant regeneration (self-renewal) of MM cells in inflammatory microenvironments. In addition to recurrent DNA mutations and epigenetic deregulation, inflammatory cytokine-responsive adenosine deaminase associated with RNA (ADAR1)-mediated adenosine to inosine (A-to-I) RNA editing has emerged as a key driver of cancer relapse and progression. In MM, copy number amplification of chromosome 1q21, which contains both ADAR1 and interleukin-6 receptor (IL-6R) gene loci, portends a poor prognosis. Thus, we hypothesized that ADAR1 copy number amplification combined with inflammatory cytokine activation of ADAR1 stimulates malignant regeneration of MM and therapeutic resistance. Methods and Results: Analysis of MMRF CoMMpass RNA sequencing (RNA-seq) data revealed that high ADAR1 expression (n=162 patients) correlated with significantly reduced progression-free and overall survival compared with a low ADAR1 subset (n=159 patients). In contrast to lentiviral ADAR1 shRNA knockdown and overexpression of an editase defective ADAR1 mutant (ADAR1E912A), lentiviral wild-type ADAR1 overexpression enhanced editing of GLI1, a Hedgehog (Hh) pathway transcriptional activator and self-renewal agonist. Editing of GLI1 transcripts enhanced GLI transcriptional activity in luciferase reporter assays, and promoted lenalidomide resistance in vitro. Finally, lentiviral shRNA ADAR1 knockdown reduced regeneration of high-risk MM in humanized serial transplantation mouse models, indicative of reduced malignant self-renewal capacity. Whole-transcriptome RNA-sequencing of primary samples after lentiviral shRNA knockdown of ADAR1 revealed specific modulation of extracellular and immune response genes, while overexpression of wild-type versus edited GLI1 elicited distinct gene expression changes in human myeloma cells analyzed using NanoString nCounter assays. These data demonstrate that ADAR1 promotes malignant self-renewal of MM and, if selectively inhibited, may prevent progression and relapse through modulation of extracellular and immune response genes. Conclusions: Deregulated RNA editing, driven by aberrant ADAR1 activation, represents a unique source of transcriptomic and proteomic diversity, resulting in self-renewal of MM cells in inflammatory microenvironments. In summary, both genetic (1q21 amplification) and microenvironmental factors (inflammatory cytokines, IMiDs) combine to drive GLI1-dependent malignant regeneration in MM. Thus, ADAR1 represents both a vital prognostic biomarker and therapeutic target in MM. Citation Format: Leslie A. Crews, Elisa Lazzari, Phoebe K. Mondala, Nathaniel Delos Santos, Amber Miller, Gabriel Pineda, Qingfei Jiang, Anusha-Preethi Ganesan, Christina Wu, Caitlin Costello, Mark Minden, Raffaella Chiaramonte, A. Keith Stewart, Catriona H. M. Jamieson. Down-modulation of ADAR1-mediated GLI1 editing alters extracellular and immune response genes 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 4437.