Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia
| Autor: | Chiara Galloni, Manuela Mancini, Elisa Leo, Enza Barbieri, Ilaria Iacobucci, Michela Aluigi, Enrica Borsi, Nevena Veljkovic, Maria Alessandra Santucci |
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| Přispěvatelé: | Manuela Mancini, Nevena Veljkovic, Elisa Leo, Michela Aluigi, Enrica Borsi, Chiara Galloni, Ilaria Iacobucci, Enza Barbieri, Maria Alessandra Santucci |
| Rok vydání: | 2012 |
| Předmět: |
EPIGENETIC MODIFICATIONS
Chromatin Immunoprecipitation Cytoplasm Fusion Proteins bcr-abl FoxO3a Biology Biochemistry Cell Line Dioxygenases Epigenesis Genetic 03 medical and health sciences Histone H3 Mice 0302 clinical medicine chronic myeloid leukemia hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive Proto-Oncogene Proteins Transcriptional regulation Animals Immunoprecipitation BIM Epigenetics Molecular Biology Transcription factor 030304 developmental biology 0303 health sciences CHRONIC MYELOID LEUKEMIA TET2 Myeloid leukemia Cell Biology Fusion protein DNA-Binding Proteins 030220 oncology & carcinogenesis Cancer research Chromatin immunoprecipitation Tyrosine kinase Bcr-Abl |
| Zdroj: | Journal of Cellular Biochemistry |
| ISSN: | 1097-4644 |
| Popis: | The loss-of-function of teneleven-translocation (TET) 2, a Fe2+-oxoglutarate-dependent dioxygenase catalyzing 5 methyl cytosine (5mC) conversion into 5-hydroxymethylcytosine (5hmC), contributes to the hematopoietic transformation in vivo. The aim of our study was to elucidate its role in the phenotype of chronic myeloid leukemia (CML), a myeloproliferative disease caused by the Bcr-Abl rearranged gene. We first confirmed TET2 interaction with the Bcr-Abl protein predicted by a Fourier-based bioinformatic method. Such interaction led to TET2 cytoplasmatic compartmentalization in a complex tethered by the fusion protein tyrosine kinase (TK) and encompassing the Forkhead box O3a (FoxO3a) transcription factor. We then focused the impact of TET2 loss-of-function on epigenetic transcriptional regulation of Bcl2-interacting mediator (BIM), a pro-apoptotic protein transcriptionally regulated by FoxO3a. BIM downregulation is a critical component of CML progenitor extended survival and is also involved in the disease resistance to imatinib (IM). Here we reported that TET2 release from Bcr-Abl protein following TK inhibition in response to IM triggers a chain of events including TET2 nuclear translocation, re-activation of its enzymatic function at 5mC and recruitment at the BIM promoter followed by BIM transcriptional induction. 5hmC increment following TET2 re-activation was associated with the reduction of histone H3 tri-methylation at lysine 9 (H3K9me3), which may contribute with DNA de-methylation reported elsewhere to recast a permissive epigenetic landscape for FoxO3a transcriptional activity. J. Cell. Biochem. 113: 27652774, 2012. (c) 2012 Wiley Periodicals, Inc. |
| Databáze: | OpenAIRE |
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