hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival. Blood 2018 Apr 05;131(14):1532-1544
Date
02/14/2018Pubmed ID
29437554Pubmed Central ID
PMC6027092DOI
10.1182/blood-2017-05-783845Scopus ID
2-s2.0-85047638589 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
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, Holyoake TLAuthor
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Proliferation
Cell Survival
E2F1 Transcription Factor
Early Growth Response Protein 1
Female
Gene Expression Regulation, Leukemic
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Male
Mice, Knockout
MicroRNAs
Neoplasm Proteins
Neoplastic Stem Cells
RNA, Neoplasm
Signal Transduction
Up-Regulation
