title: TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia.
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.
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Willer
authors.affiliation: 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.
authors.forename: J S
authors.initials: JS
authors.lastname: Jakobsen
authors.affiliation: 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.
authors.forename: E
authors.initials: E
authors.lastname: Ohlsson
authors.affiliation: 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.
authors.forename: N
authors.initials: N
authors.lastname: Rapin
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Waage
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Billing
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Karlsson
authors.affiliation: 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.
authors.forename: B T
authors.initials: BT
authors.lastname: Porse
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002453:Cell Cycle; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005801:Genes, Homeobox; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D012097:Repressor Proteins; C097504:TGIF1 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase