title: BCR-ABL/GATA1/miR-138 mini circuitry contributes to the leukemogenesis of chronic myeloid leukemia.
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.
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Dou
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
authors.forename: C-S
authors.initials: CS
authors.lastname: Chim
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Yu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology; D001665:Binding Sites; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016366:Open Reading Frames; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl