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hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.

Authors
  • Pellicano, Francesca1
  • Park, Laura1
  • Hopcroft, Lisa E M1
  • Shah, Mansi M1
  • Jackson, Lorna1
  • Scott, Mary T1
  • Clarke, Cassie J1
  • Sinclair, Amy1
  • Abraham, Sheela A1
  • Hair, Alan1
  • Helgason, G Vignir1
  • Aspinall-O'Dea, Mark2
  • Bhatia, Ravi3
  • Leone, Gustavo4
  • Kranc, Kamil R5
  • Whetton, Anthony D2
  • Holyoake, Tessa L1
  • 1 Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom. , (United Kingdom)
  • 2 Stem Cell and Leukaemia Proteomics Laboratory, Faculty Institute of Cancer Sciences, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom. , (United Kingdom)
  • 3 Division of Hematology and Oncology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL.
  • 4 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC; and.
  • 5 MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Apr 05, 2018
Volume
131
Issue
14
Pages
1532–1544
Identifiers
DOI: 10.1182/blood-2017-05-783845
PMID: 29437554
Source
Medline
Language
English
License
Unknown

Abstract

Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of hsa-mir183, the downregulation of its direct target early growth response 1 (EGR1), and, as a consequence, upregulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPCs. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPCs, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication. © 2018 by The American Society of Hematology.

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