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BCR-ABL/GATA1/miR-138 mini circuitry contributes to the leukemogenesis of chronic myeloid leukemia

Oncogene volume 33, pages 44–54 (2014)Cite this article

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Abstract

Abnormal expression of microRNAs (miRNAs) has been implicated in carcinogenesis. Here we report a novel BCR (breakpoint cluster region)-ABL (c-abl oncogene 1, non-receptor tyrosine kinase)/GATA1/microRNA-138 (miR-138) circuitry in chronic myeloid leukemia (CML). miR-138 expression is downregulated in K562 cells and primary CML samples, which is restored after imatinib treatment. The tumor suppressor activity of miR-138 is demonstrated by the induction of cell cycle arrest at G0/G1, inhibition of cell proliferation and colony forming unit granulocyte-macrophage colony formation and enhanced imatinib-induced apoptosis in K562 and Ku812 cells overexpressing miR-138. Moreover, overexpression of miR-138 led to the downregulation of BCR-ABL. Based on luciferase assay, ABL and BCR-ABL are shown to be the target genes regulated by miR-138. Furthermore, miR-138 binding to ABL was shown to localize to the coding region instead of 3′-untranslated regions (3′-UTR) of ABL mRNA. In addition, CCND3 is another target of miR-138, which represses CCND3 expression by binding to its 3′-UTR. Finally, upregulation of miR-138 upon imatinib treatment is associated with the enhancement of GATA1 activity, which binds to the miR-138 promoter. In conclusion, miR-138 is a tumor suppressor miRNA underexpressed in CML. miR-138 represses expression of both BCR-ABL and CCND3 via binding to the coding region and 3′-UTR, respectively. miR-138 expression is activated by GATA1, which in turn is repressed by BCR-ABL. Therefore, miR-138, by virtue of a BCR-ABL/GATA1/miR-138 circuitry, is a tumor suppressor miRNA implicated in the pathogenesis of CML and its clinical response to imatinib.

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Acknowledgements

We thank C Li (Beijing Institute of Radiation Medicine, Beijing, China) for kindly providing the GATA1 expression vector. This work was supported partially by Chinese State Key Projects for Basic Research (2005CB522408 and 2010CB912801), Chinese National Natural Science Foundation Projects (90919044, 81072021, 30971297, and 81170518), High and New Technology Program of PLA (2010gxjs091) and Capital Medical Development Scientific Research Fund (no. 2007-2040).

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  1. C Xu and H Fu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Chinese PLA General Hospital, Beijing, China

    C Xu, L Gao, L Wang, W Wang, J Li, Y Li, L Dou, X Gao, X Luo, Y Jing & L Yu

  2. Department of Biochemistry and Molecular Biology, Beijing Institute of Radiation Medicine, Beijing, China

    H Fu & X Zheng

  3. Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China

    C-S Chim

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  1. C Xu
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Correspondence to X Zheng or L Yu.

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Xu, C., Fu, H., Gao, L. et al. BCR-ABL/GATA1/miR-138 mini circuitry contributes to the leukemogenesis of chronic myeloid leukemia. Oncogene 33, 44–54 (2014). https://doi.org/10.1038/onc.2012.557

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