Qingfei Jiang1, Jane Isquith2, Maria Anna Zipeto2, Raymond H Diep2, Jessica Pham2, Nathan Delos Santos2, Eduardo Reynoso2, Julisia Chau2, Heather Leu2, Elisa Lazzari2, Etienne Melese3, Wenxue Ma2, Rongxin Fang4, Mark Minden5, Sheldon Morris6, Bing Ren7, Gabriel Pineda8, Frida Holm2, Catriona Jamieson9. 1. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: q1jiang@ucsd.edu. 2. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. 3. Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. 4. Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA. 5. Princess Margaret Hospital, Toronto, ON M5T 2M9, Canada. 6. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA. 7. Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA, USA; Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA. 8. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Health Sciences, School of Health and Human Services, National University, San Diego, CA, USA. 9. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: cjamieson@ucsd.edu.
Abstract
Adenosine deaminase associated with RNA1 (ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Moreover, A-to-I editing of both the MDM2 regulatory microRNA and its binding site within the 3' UTR region stabilizes MDM2 transcripts, thereby enhancing blast crisis progenitor propagation. These data reveal a dual mechanism governing malignant transformation of progenitors that is predicated on hyper-editing of cell-cycle-regulatory miRNAs and the 3' UTR binding site of tumor suppressor miRNAs.
pan class="Gene">Adenosine deaminase associated with RNA1 (pan class="Gene">ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Moreover, A-to-I editing of both the MDM2 regulatory microRNA and its binding site within the 3' UTR region stabilizes MDM2 transcripts, thereby enhancing blast crisis progenitor propagation. These data reveal a dual mechanism governing malignant transformation of progenitors that is predicated on hyper-editing of cell-cycle-regulatory miRNAs and the 3' UTR binding site of tumor suppressor miRNAs.
Authors: Xinxin Peng; Xiaoyan Xu; Yumeng Wang; David H Hawke; Shuangxing Yu; Leng Han; Zhicheng Zhou; Kamalika Mojumdar; Kang Jin Jeong; Marilyne Labrie; Yiu Huen Tsang; Minying Zhang; Yiling Lu; Patrick Hwu; Kenneth L Scott; Han Liang; Gordon B Mills Journal: Cancer Cell Date: 2018-04-26 Impact factor: 31.743
Authors: Wendy Béguelin; Matt Teater; Micah D Gearhart; María Teresa Calvo Fernández; Rebecca L Goldstein; Mariano G Cárdenas; Katerina Hatzi; Monica Rosen; Hao Shen; Connie M Corcoran; Michelle Y Hamline; Randy D Gascoyne; Ross L Levine; Omar Abdel-Wahab; Jonathan D Licht; Rita Shaknovich; Olivier Elemento; Vivian J Bardwell; Ari M Melnick Journal: Cancer Cell Date: 2016-08-08 Impact factor: 31.743
Authors: Maria Anna Zipeto; Angela C Court; Anil Sadarangani; Nathaniel P Delos Santos; Larisa Balaian; Hye-Jung Chun; Gabriel Pineda; Sheldon R Morris; Cayla N Mason; Ifat Geron; Christian Barrett; Daniel J Goff; Russell Wall; Maurizio Pellecchia; Mark Minden; Kelly A Frazer; Marco A Marra; Leslie A Crews; Qingfei Jiang; Catriona H M Jamieson Journal: Cell Stem Cell Date: 2016-06-09 Impact factor: 24.633