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BCR-ABL mediated repression of miR-223 results in the activation of MEF2C and PTBP2 in chronic myeloid leukemia

Leukemia volume 27, pages 1578–1580 (2013)Cite this article

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Posttranscriptional regulation by microRNAs (miRNAs) has an important role in modulating the gene regulatory network as miRNAs can negatively regulate protein translation by binding to the complementary sequences of the 3′ untranslated region (UTR) of messenger RNA.1 As in other leukemia, abnormal expression of several miRNAs is reported in chronic myeloid leukaemia (CML).2 Downregulation of miR-10a leads to abnormal proliferation of CML cells through regulation of USF2 gene expression, whereas forced expression of miR-328 that is lost in the blast phase of the disease rescues C/EBP alpha-driven granulocytic maturation and impairs survival of CML cells.3, 4 Recently, one of the miRNA that is attracting considerable attention in hematopoiesis is miR-223 as it resembles a myeloid gene and its expression is known to increase towards myeloid differentiation. Expression of miR-223, which was identified bioinformatically, is controlled by three transcription factors, C/EBPα, PU.1 and NFI-A. C/EBP-α and PU.1 positively regulates miR-223, whereas NFI-A competes for C/EBPα binding site and maintains miR-223 at low levels.5, 6 BCR-ABL inhibits the translation of C/EBPα mRNA by stabilizing the RNA-binding protein hnRNP E2.7 As CML is characterized by chronic granulocytic maturation arrest and the transcription factors involved in miR-223 expression are deregulated in CML, we predicted that miR-223 may have a role in CML disease biology.

MiR-223 relative expression was correlated in CML with the available clinical parameters. Among the available clinical data, sokal score and neutrophil percentage were found to be significant. MiR-223 expression was positively correlated with mature neutrophil percentage, and this data also supports the role of miR-223 in granulocytic maturation as shown by Fazi et al.6 (data not shown). Spearman’s correlation test demonstrated the existence of a negative correlation between miR-223 expression levels and sokal score. This suggests that miR-223 expression is negatively correlated with disease risk (Figure 1c) and may be used as a disease-risk prediction marker.

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Acknowledgements

We thank Dr Clara Nervi, Department of Histology and Medical Embryology, University La Sapienza, Rome, Italy, for the lentiviral vector construct carrying miR-223. We thank Dr Eugene Makeyev, School of Biological Sciences, Nanyang Technological University, Singapore for PTBP2 3′ UTR luciferase construct. We also thank Professor Catherine M Verfaillie, KU Leuven, Belgium, for her critical review of the manuscript. We also thank Ms Nivedita Kuila and Mr Pulak Mohanty for their assistance. This work was supported by the Institutional core grant. SA is supported by fellowship from the Council of Scientific and Industrial Research (CSIR), India. SS is supported by fellowship from the University Grants Commission (UGC), India.

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  1. Institute of Life Sciences, Bhubaneswar, India

    S Agatheeswaran, S Singh & S Chakraborty

  2. Sparsh Hospital and Critical Care, Bhubaneswar, India

    S Biswas & G Biswas

  3. Department of Clinical Haematology, SCB Medical College, Cuttack, India

    N Chandra Pattnayak

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  1. S Agatheeswaran
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Correspondence to S Chakraborty.

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Agatheeswaran, S., Singh, S., Biswas, S. et al. BCR-ABL mediated repression of miR-223 results in the activation of MEF2C and PTBP2 in chronic myeloid leukemia. Leukemia 27, 1578–1580 (2013). https://doi.org/10.1038/leu.2012.339

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