期刊
HAEMATOLOGICA
卷 103, 期 12, 页码 2016-2025出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.193086
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资金
- Ministry of Education Youth and Sports [MSMT LH15104]
- Charles University [GAUK 178215, GACR 18-18407S]
- Czech Ministry of Health [00023736]
- Charles University Research Centers grant [UNCE/MED/016]
- NCI-NIH [CA163800]
- [Q26]
- NATIONAL CANCER INSTITUTE [R01CA163800] Funding Source: NIH RePORTER
The fusion oncoprotein BCR-ABL1 exhibits aberrant tyrosine kinase activity and it has been proposed that it deregulates signaling networks involving both transcription factors and non-coding microRNAs that result in chronic myeloid leukemia (CML). Previously, microRNA expression profiling showed deregulated expression of miR150 and miR-155 in CML. In this study, we placed these findings into the broader context of the MYC/miR-150/MYB/miR-155/PU. 1 oncogenic network. We propose that up-regulated MYC and miR-155 in CD34(+) leukemic stem and progenitor cells, in concert with BCR-ABL1, impair the molecular mechanisms of myeloid differentiation associated with low miR-150 and PU.1 levels. We revealed that MYC directly occupied the -11.7 kb and -0.35 kb regulatory regions in the MIR150 gene. MYC occupancy was markedly increased through BCR-ABL1 activity, causing inhibition of MIR150 gene expression in CML CD34(+) and CD34-cells. Furthermore, we found an association between reduced miR-150 levels in CML blast cells and their resistance to tyrosine kinase inhibitors (TKIs). Although TKIs successfully disrupted BCR-ABL1 kinase activity in proliferating CML cells, this treatment did not efficiently target quiescent leukemic stem cells. The study presents new evidence regarding the MYC/miR-150/MYB/miR-155/PU. 1 leukemic network established by aberrant BCR-ABL1 activity. The key connecting nodes of this network may serve as potential druggable targets to overcome resistance of CML stem and progenitor cells.
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