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

Francesca Pellicano, Laura Park, Lisa E.M. Hopcroft, Mansi M. Shah, Lorna Jackson, Mary T. Scott, Cassie J. Clarke, Amy Sinclair, Sheela A. Abraham, Alan Hair, G. Vignir Helgason, Mark Aspinall-O'Dea, Ravi Bhatia, Gustavo Leone, Kamil R. Kranc, Anthony D. Whetton and Tessa L. Holyoake

Key points

  • hsa-mir183/EGR1/E2F1 is a novel and critical factor for CML SPC survival

  • E2F1 plays a pivotal role in regulating CML SPC proliferation status

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.

  • Submitted May 12, 2017.
  • Accepted January 5, 2018.