1. hsa-mir183/EGR1 -mediated regulation of E2F1 is required for CML stem/progenitor cell survival.
- Author
-
Pellicano F, Park L, Hopcroft LEM, Shah MM, Jackson L, Scott MT, Clarke CJ, Sinclair A, Abraham SA, Hair A, Helgason GV, Aspinall-O'Dea M, Bhatia R, Leone G, Kranc KR, Whetton AD, and Holyoake TL
- Subjects
- Animals, Cell Proliferation, Cell Survival, E2F1 Transcription Factor genetics, Early Growth Response Protein 1 genetics, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Mice, Knockout, MicroRNAs genetics, Neoplasm Proteins genetics, Neoplastic Stem Cells pathology, RNA, Neoplasm genetics, Signal Transduction, E2F1 Transcription Factor biosynthesis, Early Growth Response Protein 1 metabolism, Gene Expression Regulation, Leukemic, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, MicroRNAs metabolism, Neoplasm Proteins metabolism, Neoplastic Stem Cells metabolism, RNA, Neoplasm metabolism, Up-Regulation
- 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.)
- Published
- 2018
- Full Text
- View/download PDF