Identification of MLL-fusion/MYC⊣miR-26⊣TET1 signaling circuit in MLL-rearranged leukemia. Issue 2 (28th March 2016)

• Record Type: Journal Article
• Authors: Huang, Hao; Jiang, Xi; Wang, Jinhua; Li, Yuanyuan; Song, Chun-Xiao; Chen, Ping; Li, Shenglai; Gurbuxani, Sandeep; Arnovitz, Stephen; Wang, Yungui; Weng, Hengyou; Neilly, Mary Beth; He, Chuan; Li, Zejuan; Chen, Jianjun
• Is Part Of: Cancer letters. Volume 372:Issue 2(2016)
• Page Start: 157
• Page End: 165
• Publication Date: 2016-03-28
• Subjects: MLL-rearranged leukemia -- miR-26a -- TET1 -- MYC -- Post-transcription regulation; MLL mixed lineage leukemia -- AML acute myeloid leukemia -- qRT-PCR quantitative real-time polymerase chain reaction -- ChIP chromatin immunoprecipitation -- BM bone marrow -- BMT bone marrow transplantation -- PB peripheral blood -- SP spleen -- SAM Significance Analysis of Microarrays -- Lin- lineage-negative; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.12.032
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: miR-26a is significantly down-regulated in MLL -rearranged AML. miR-26a plays a critical anti-leukemic function both in vitro and in vivo. TET1 is a direct target gene of miR-26a in MLL -rearranged AML. TET1 's overexpression and oncogenic role in MLL AML rely on suppression of miR-26a. MYC mediates the transcriptional suppression of miR-26a in MLL -rearranged AML. 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.