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.
Highlights
Chronic myeloid leukemia (CML) is caused by the constitutively active BCR-ABL tyrosine kinase which is a product of the Philadelphia chromosome (t (9; 22))
CML stem cells are known to reside in the lin(−) CD34+CD38− population and recently it was reported that the progenitor cells acquire stem cell properties which results in the progression of the disease[3]
Our data is concurrent with the earlier reports which suggest that higher levels of CD34+ cells are present in CML patients
Summary
Chronic myeloid leukemia (CML) is caused by the constitutively active BCR-ABL tyrosine kinase which is a product of the Philadelphia chromosome (t (9; 22)). It was reported earlier that the granulocyte-macrophage progenitor population acquires stem cell-like properties during CML blast crisis[3]. A small molecule BCR-ABL specific tyrosine kinase inhibitor (TKI), is the first-line of therapy for CML and helps to achieve a complete cytogenetic response (CCR) in more than 80% of the patients[4]. It was observed earlier that lin(−)CD34+population, which includes HSCs and progenitors, were resistant to imatinib mediated cell death in the presence of growth factors[7,8]. It was observed that the downregulation of miR-328 in CML-BC CD34+cells favours the hnRNP E2 mediated translation inhibition of C/EBPαmRNA that results in differentiation arrested myeloid cells[14]. Given that a single miRNA can control a set of target genes and each gene can be targeted by multiple miRNAs we decided to identify the complex miRNA–gene regulatory networks present in the CML lin(−) cells which may help to delineate the disease further
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