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

Pellicano, F. et al. (2018) Hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival. Blood, 131(14), pp. 1532-1544. (doi:10.1182/blood-2017-05-783845) (PMID:29437554) (PMCID:PMC6027092)

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Abstract

Chronic myeloid leukemia (CML) stem/progenitor cells (SPC) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPC 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 up-regulation of hsa-mir183, the down-regulation of its direct target EGR1 and, as a consequence, up-regulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPC. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPC, 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Scott, Dr Mary and Holyoake, Professor Tessa and Clarke, Dr Cassie and Park, Ms Laura and Hair, Dr Alan and Abraham, Dr Sheela and Shah, Dr Mansi and Sinclair, Miss Amy and Jackson, Lorna and Pellicano, Dr Francesca and Helgason, Dr Vignir and Kranc, Professor Kamil and Hopcroft, Dr Lisa
Authors: Pellicano, F., Park, L., Hopcroft, L. E.M., Shah, M. M., Jackson, L., Scott, M. T., Clarke, C. J., Sinclair, A., Abraham, S. A., Hair, A., Helgason, G. V., Aspinall-O'Dea, M., Bhatia, R., Leone, G., Kranc, K. R., Whetton, A. D., and Holyoake, T. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:05 February 2018
Copyright Holders:Copyright © 2018 The American Society of Hematology
First Published:First published in Blood 131(14):1532-1544
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
498551Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CRUK)11008RI CANCER SCIENCES
591161Investigation of the role of E2F1 in CML Leukaemic Stem Cells (LSC).Tessa HolyoakeThe Kay Kendall Leukaemia Fund (KENDALL)KKL690RI CANCER SCIENCES
608811Autophagy Inhibition Combined with Targeted Therapy for Elimination of CML Stem Cells.Vignir HelgasonThe Kay Kendall Leukaemia Fund (KENDALL)KKL698RI CANCER SCIENCES
679891Targeting p53, cMyc and PRC2 regulatory hubs: A systematic and stratified approach to deliver new therapeutics for CMLDavid VetrieBloodwise (BLOODWIS)14033ICS - EPIGENETICS
500231BBSRC Doctoral Training Grant 2009-15Katherine WestBiotechnology and Biological Sciences Research Council (BBSRC)BB/F016050/1RI CANCER SCIENCES
655501Modulation of H3K27 methylation to eradicate TKI-persistant CML stem cellsDavid VetrieBloodwise (BLOODWIS)14005ICS - EPIGENETICS
634291Dual targeting of p53 and c-myc to eradicate CML stem cellsTessa HolyoakeBloodwise (BLOODWIS)13035ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
494701A phosphoproteomic investigation of key BCR-ABL mediated signally pathways in CML stem cells: where does tyrosine kinase inhibitor resistance lie?Tessa HolyoakeBloodwise (LRF)08071RI CANCER SCIENCES
767002Exposing the interdependent mechanisms of the leukaemic stem cell and the leukaemic niche in chronic myeloid leukaemia using integrative network and systems biologyLisa HopcroftThe Kay Kendall Leukaemia Fund (KENDALL)KKL1148RI CANCER SCIENCES
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES
606412MRC Doctoral Training Grant 2012-16Margaret MacLeanMedical Research Council (MRC)MR/K500847/1RI CARDIOVASCULAR & MEDICAL SCIENCES