期刊
BLOOD
卷 131, 期 14, 页码 1532-1544出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-05-783845
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资金
- Beatson Institute for Cancer Research Animal Unit
- Cancer Research UK [C11074/A11008]
- Elimination of Leukaemia Fund [F217]
- Kay Kendall Leukaemia Fund [KKL690, KKL501, KKL1148, KKL698]
- Biotechnology and Biological Sciences Research Council [BB/F016050/1]
- Bloodwise [14005, 13035, 08071, 08004, 14033]
- MRC DTP Precision Medicine Studentship [MR/K500847/1]
- Scottish Cancer Foundation
- Howat Foundation
- Chief Scientist's Office, Scotland
- SPIRIT Trials Management Group
- MRC [MR/P010008/1, MR/N00583X/1] Funding Source: UKRI
- Barts Charity [MGU0418] Funding Source: researchfish
- Cancer Research UK [14633, 11008, 26787] Funding Source: researchfish
- Medical Research Council [1515962, MR/P010008/1, MR/N00583X/1] Funding Source: researchfish
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 hsamir183, 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.
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