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Expression of functionally important genes is often tightly regulated at both transcriptional and post-transcriptional levels. We reported previously that TET1, the founding member of the TET methylcytosine dioxygenase family, plays an essential oncogenic role in MLL-rearranged acute myeloid leukemia (AML), where it is overexpressed owing to MLL-fusion-mediated direct up-regulation at the transcriptional level. Here we show that the overexpression of TET1 in MLL-rearranged AML also relies on the down-regulation of miR-26a, which directly negatively regulates TET1 expression at the post-transcriptional level. Through inhibiting expression of TET1 and its downstream targets, forced expression of miR-26a significantly suppresses the growth/viability of human MLL-rearranged AML cells, and substantially inhibits MLL-fusion-mediated mouse hematopoietic cell transformation and leukemogenesis. Moreover, c-Myc, an oncogenic transcription factor up-regulated in MLL-rearranged AML, mediates the suppression of miR-26a expression at the transcriptional level. Collectively, our data reveal a previously unappreciated signaling pathway involving the MLL-fusion/MYC⊣miR-26a⊣TET1 signaling circuit, in which miR-26a functions as an essential tumor-suppressor mediator and its transcriptional repression is required for the overexpression and oncogenic function of TET1 in MLL-rearranged AML. Thus, restoration of miR-26a expression/function holds therapeutic potential to treat MLL-rearranged AML.

Original publication

DOI

10.1016/j.canlet.2015.12.032

Type

Journal article

Journal

Cancer Lett

Publication Date

28/03/2016

Volume

372

Pages

157 - 165

Keywords

MLL-rearranged leukemia, MYC, Post-transcription regulation, TET1, miR-26a, 3' Untranslated Regions, Animals, Binding Sites, Bone Marrow Transplantation, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cell Transformation, Neoplastic, DNA-Binding Proteins, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Leukemic, Gene Fusion, Gene Rearrangement, Histone-Lysine N-Methyltransferase, Humans, Leukemia, Myeloid, Acute, Mice, Inbred C57BL, MicroRNAs, Mixed Function Oxygenases, Myeloid-Lymphoid Leukemia Protein, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-myc, Signal Transduction, Time Factors, Transcription, Genetic, Transfection