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

Oncogene. 2014 Jan 2;33(1):44-54. doi: 10.1038/onc.2012.557. Epub 2012 Dec 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Base Sequence
  • Benzamides / pharmacology
  • Binding Sites
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Cell Proliferation
  • Down-Regulation
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • G1 Phase Cell Cycle Checkpoints
  • GATA1 Transcription Factor / metabolism*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Open Reading Frames
  • Piperazines / pharmacology
  • Promoter Regions, Genetic
  • Pyrimidines / pharmacology
  • RNA Interference


  • Antineoplastic Agents
  • Benzamides
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • MIRN138 microRNA, human
  • MicroRNAs
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl