TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia
| Autor: | Lars Bullinger, Stefan Karlsson, Nicolas Rapin, Johannes Waage, Anton Willer, Bo T. Porse, Ewa Ohlsson, Janus S. Jakobsen, Matilda Billing |
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| Rok vydání: | 2014 |
| Předmět: |
Chromatin Immunoprecipitation
Cancer Research Transcription Genetic Protein family Cellular differentiation Bone Marrow Cells Biology Transforming Growth Factor beta1 Mice hemic and lymphatic diseases medicine Animals Humans Myeloid Ecotropic Viral Integration Site 1 Protein neoplasms Transcription factor Regulator gene Homeodomain Proteins Genetics Regulation of gene expression Gene Expression Regulation Leukemic Gene Expression Profiling Cell Cycle Genes Homeobox Myeloid leukemia Cell Differentiation Histone-Lysine N-Methyltransferase Hematology Flow Cytometry medicine.disease Neoplasm Proteins Mice Inbred C57BL Repressor Proteins Gene expression profiling Leukemia Myeloid Acute Leukemia Treatment Outcome Oncology Cancer research Myeloid-Lymphoid Leukemia Protein Transcription Factors |
| Zdroj: | Leukemia. 29:1018-1031 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2014.307 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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