12
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia.

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Members of the TALE (three-amino-acid loop extension) family of atypical homeodomain-containing transcription factors are important downstream effectors of oncogenic fusion proteins involving the mixed lineage leukemia (MLL) gene. A well-characterized member of this protein family is MEIS1, which orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). TGIF1/TGIF2 are relatively uncharacterized TALE transcription factors, which, in contrast to the remaining family, have been shown to act as transcriptional repressors. Given the general importance of this family in malignant hematopoiesis, we therefore tested the potential function of TGIF1 in the maintenance of MLL-rearranged AML. Gene expression analysis of MLL-rearranged patient blasts demonstrated reduced TGIF1 levels, and, in accordance, we find that forced expression of TGIF1 in MLL-AF9-transformed cells promoted differentiation and cell cycle exit in vitro, and delayed leukemic onset in vivo. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating with MEIS1-bound regions in a competitive manner and that the MEIS1:TGIF1 ratio influence the clinical outcome. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for leukemic maintenance and provide novel insights into the regulatory gene expression circuitries in MLL-rearranged AML.

          Related collections

          Author and article information

          Journal
          Leukemia
          Leukemia
          1476-5551
          0887-6924
          May 2015
          : 29
          : 5
          Affiliations
          [1 ] 1] The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark [2] Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark [3] Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
          [2 ] 1] The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark [2] Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark [3] Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark [4] The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark.
          [3 ] Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund, Sweden.
          [4 ] Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
          Article
          leu2014307
          10.1038/leu.2014.307
          25349154
          2519881d-0850-415b-bc84-507e5bf02a7e
          History

          Comments

          Comment on this article