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Reversal of malignant ADAR1 splice isoform switching with Rebecsinib.
Crews, Leslie A; Ma, Wenxue; Ladel, Luisa; Pham, Jessica; Balaian, Larisa; Steel, S Kathleen; Mondala, Phoebe K; Diep, Raymond H; Wu, Christina N; Mason, Cayla N; van der Werf, Inge; Oliver, Isabelle; Reynoso, Eduardo; Pineda, Gabriel; Whisenant, Thomas C; Wentworth, Peggy; La Clair, James J; Jiang, Qingfei; Burkart, Michael D; Jamieson, Catriona H M.
Afiliación
  • Crews LA; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Ma W; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Ladel L; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Pham J; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Balaian L; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Steel SK; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Mondala PK; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Diep RH; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Wu CN; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Mason CN; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • van der Werf I; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Oliver I; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Reynoso E; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Pineda G; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Whisenant TC; Center for Computational Biology & Bioinformatics (CCBB), Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Wentworth P; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • La Clair JJ; Departments of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • Jiang Q; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA.
  • Burkart MD; Departments of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • Jamieson CHM; Department of Medicine, Division of Regenerative Medicine, Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: cjamieson@health.ucsd.edu.
Cell Stem Cell ; 30(3): 250-263.e6, 2023 03 02.
Article en En | MEDLINE | ID: mdl-36803553
ABSTRACT
Adenosine deaminase acting on RNA1 (ADAR1) preserves genomic integrity by preventing retroviral integration and retrotransposition during stress responses. However, inflammatory-microenvironment-induced ADAR1p110 to p150 splice isoform switching drives cancer stem cell (CSC) generation and therapeutic resistance in 20 malignancies. Previously, predicting and preventing ADAR1p150-mediated malignant RNA editing represented a significant challenge. Thus, we developed lentiviral ADAR1 and splicing reporters for non-invasive detection of splicing-mediated ADAR1 adenosine-to-inosine (A-to-I) RNA editing activation; a quantitative ADAR1p150 intracellular flow cytometric assay; a selective small-molecule inhibitor of splicing-mediated ADAR1 activation, Rebecsinib, which inhibits leukemia stem cell (LSC) self-renewal and prolongs humanized LSC mouse model survival at doses that spare normal hematopoietic stem and progenitor cells (HSPCs); and pre-IND studies showing favorable Rebecsinib toxicokinetic and pharmacodynamic (TK/PD) properties. Together, these results lay the foundation for developing Rebecsinib as a clinical ADAR1p150 antagonist aimed at obviating malignant microenvironment-driven LSC generation.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Adenosina Desaminasa Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Stem Cell Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Adenosina Desaminasa Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Stem Cell Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos