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Published on: June 15, 2016
Identification and functional characterization of the miRNA-gene regulatory network in chronic myeloid leukemia
S Agatheeswaran1, N C Pattnayak2, S Chakraborty1
1Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, India.
Abstract:
Chronic myeloid leukemia (CML) is maintained by leukemic stem cells (LSCs) which are resistant to the existing TKI therapy. Hence a better understanding of the CML LSCs is necessary to eradicate these cells and achieve complete cure. Using the miRNA-gene interaction networks from the CML lin(-) cells we identified a set of up/down-regulated miRNAs and corresponding target genes. Association studies (Pearson correlation) from the miRNA and gene expression data showed that miR-1469 and miR-1972 have significantly higher number of target genes, 75 and 50 respectively. We observed that miR-1972 induces G2-M cell cycle arrest and miR-1469 moderately arrested G1 cell cycle when overexpressed in KCL22 cells. We have earlier shown that a combination of imatinib and JAK inhibitor I can significantly bring down the proliferation of CML lineage negative cells. Here we observed that imatinib and JAK inhibitor I combination restored the expression pattern of the down-regulated miRNAs in primary CML lin(-) cells. Thus effective manipulation of the deregulated miRNAs can restore the miRNA-mRNA networks that can efficiently inhibit CML stem and progenitor cells and alleviate the disease.
Insights
Targeting specific microRNAs (miRNAs) like miR-1469 and miR-1972 could be a novel strategy to eliminate resistant chronic myeloid leukemia (CML) stem cells. Restoring miRNA expression may offer a path to a complete cure for CML.
Area of Science:
- Biochemistry
- Molecular Biology
- Hematology
Background:
- Chronic myeloid leukemia (CML) is sustained by therapy-resistant leukemic stem cells (LSCs).
- Understanding CML LSCs is crucial for developing curative strategies beyond current tyrosine kinase inhibitor (TKI) treatments.
Purpose of the Study:
- To investigate the role of microRNAs (miRNAs) and their target genes in CML stem cells.
- To identify specific miRNAs that can be therapeutically manipulated to target CML LSCs.
Main Methods:
- Analysis of miRNA-gene interaction networks in CML stem cells.
- Correlation studies between miRNA and gene expression data.
- Overexpression of candidate miRNAs in CML cell lines.
- Assessment of combination therapy effects on miRNA expression patterns.
Main Results:
- miR-1469 and miR-1972 were identified as key miRNAs with numerous target genes in CML stem cells.
- Overexpression of miR-1972 induced G2-M cell cycle arrest, while miR-1469 induced G1 arrest.
- Combination therapy with imatinib and JAK inhibitor I restored downregulated miRNA expression in primary CML stem cells.
Conclusions:
- Deregulation of specific miRNAs contributes to CML stem cell maintenance.
- Targeting miR-1469 and miR-1972 offers a potential therapeutic approach for CML.
- Restoring miRNA-mRNA networks through targeted manipulation can inhibit CML stem and progenitor cells, potentially leading to disease eradication.
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