Identification of MLL-fusion/MYC⊣miR-26⊣TET1 signaling circuit in MLL-rearranged leukemia

Hao Huang, Xi Jiang, Jinhua Wang, Yuanyuan Li, Chun Xiao Song, Ping Chen, Shenglai Li, Sandeep Gurbuxani, Stephen Arnovitz, Yungui Wang, Hengyou Weng, Mary Beth Neilly, Chuan He, Zejuan Li, Jianjun Chen

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)157-165
Number of pages9
JournalCancer Letters
Volume372
Issue number2
DOIs
StatePublished - Mar 28 2016

Keywords

  • MLL-rearranged leukemia
  • MYC
  • MiR-26a
  • Post-transcription regulation
  • TET1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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