Reversal of malignant ADAR1 splice isoform switching with Rebecsinib

Cell Stem Cell. 2023 Mar 2;30(3):250-263.e6. doi: 10.1016/j.stem.2023.01.008. Epub 2023 Feb 16.


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.

Keywords: ADAR1; RNA editing; cancer stem cells; cancer therapy; hematopoiesis; leukemia stem cells; myelofibrosis; myeloproliferative neoplasms; secondary AML; splicing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Deaminase* / genetics
  • Animals
  • Hematopoietic Stem Cells*
  • Mice
  • Protein Isoforms


  • Protein Isoforms
  • Adenosine Deaminase
  • ADAR1 protein, mouse