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Haematologica 2018 Volume 103(12):2016-2025
Ferrata Storti Foundation
Chronic Myeloid Leukemia
BCR-ABL1 mediated miR-150 downregulation through MYC contributed to myeloid differentiation block and drug resistance in chronic myeloid leukemia
Klara Srutova,1 Nikola Curik,1,2 Pavel Burda,1,2 Filipp Savvulidi,2
Giovannino Silvestri,3 Rossana Trotta,4 Hana Klamova,1,5 Pavla Pecherkova,1 Zofie Sovova,1 Jitka Koblihova,1 Tomas Stopka,6 Danilo Perrotti3 and Katerina Machova Polakova1,5
SK and CN contributed equally to this work.
1Institute of Hematology and Blood Transfusion, Prague, Czech Republic; 2Institute of Pathological Physiology, First Medical Faculty, Charles University, Prague, Czech Republic; 3Department of Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, MD, USA; 4Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, MD, USA; 5Institute of Clinical and Experimental Hematology, First Medical Faculty, Charles University, Prague, Czech Republic and 6BIOCEV, First Medical Faculty, Charles University, Vestec, Czech Republic
ABSTRACT
The fusion oncoprotein BCR-ABL1 exhibits aberrant tyrosine kinase activity and it has been proposed that it deregulates signaling net- works involving both transcription factors and non-coding microRNAs that result in chronic myeloid leukemia (CML). Previously, microRNA expression profiling showed deregulated expression of miR- 150 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 quies- cent 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.
Introduction
Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease orig- inating from hematopoietic stem cells. The hallmark of CML is the presence of the BCR-ABL1 fusion gene due to the reciprocal translocation t(9;22)(q34;11). The con- stitutively active tyrosine kinase activity of the chimeric BCR-ABL1 protein causes deregulation and reprogramming of downstream signaling pathways, and drives the oncogenic process by altering cell proliferation, differentiation and survival. An understanding of CML pathogenesis consequently allowed a rational therapeutic strategy targeting BCR-ABL1 oncoprotein using tyrosine kinase inhibitors (TKIs) to be developed. The introduction of TKIs represented a breakthrough in CML ther- apy and achieved a large improvement in patient prognosis and outcome, and TKIs became the gold standard for first-line treatment.1
Correspondence:
katerina.machova@uhkt.cz
Received: March 9, 2018. Accepted: July 19, 2018. Pre-published: July 26, 2018.
doi:10.3324/haematol.2018.193086
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/12/2016
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