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 |
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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, Professor 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 > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
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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