Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia
Veljković, Nevena V.
Santucci, Maria Alessandra
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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 i...nvolved 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.
Keywords:CHRONIC MYELOID LEUKEMIA / Bcr-Abl / TET2 / BIM / FoxO3a / EPIGENETIC MODIFICATIONS
Source:Journal of Cellular Biochemistry, 2012, 113, 8, 2765-2774
- Application of the EIIP/ISM bioinformatics platform in discovery of novel therapeutic targets and potential therapeutic molecules (RS-173001)
- Universita di Bologna (RFO), Ministero della Pubblica Istruzione, Universita e Ricerca (PRIN), Fondazione del Monte di Bologna e Ravenna, BolognaAIL, COST Action [BM0801], Fondazione Umberto Veronesi