title: Identification of MLL-fusion/MYC⊣miR-26⊣TET1 signaling circuit in MLL-rearranged leukemia.
abstract: 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.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chun-Xiao
authors.initials: CX
authors.lastname: Song
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Shenglai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Yungui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Hengyou
authors.initials: H
authors.lastname: Weng
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA. Electronic address: Chen3jj@uc.edu.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D050939:Gene Fusion; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D035683:MicroRNAs; D006899:Mixed Function Oxygenases; D051788:Myeloid-Lymphoid Leukemia Protein; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C497422:KMT2A protein, human; C528163:MIRN26 microRNA, human; C489427:MYC protein, human; C462539:TET1 protein, human
keywords: MLL-rearranged leukemia; MYC; Post-transcription regulation; TET1; miR-26a