1. hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival.
- Author
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Pellicano, Francesca, Park, Laura, Hopcroft, Lisa E. M., Shah, Mansi M., Jackson, Lorna, Scott, Mary T., Clarke, Cassie J., Sinclair, Amy, Abraham, Sheela A., Hair, Alan, Helgason, G. Vignir, Aspinall-O'Dea, Mark, Bhatia, Ravi, Leone, Gustavo, Kranc, Kamil R., Whetton, Anthony D., and Holyoake, Tessa L.
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MYELOID leukemia , *STEM cells , *PROGENITOR cells , *CELL proliferation , *PROTEIN kinases - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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