Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia
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Mancini, ManuelaVeljković, Nevena V.
Leo, Elisa
Aluigi, Michela
Borsi, Enrica
Galloni, Chiara
Iacobucci, Ilaria
Barbieri, Enza
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 MODIFICATIONSSource:
Journal of Cellular Biochemistry, 2012, 113, 8, 2765-2774Funding / projects:
- Application of the EIIP/ISM bioinformatics platform in discovery of novel therapeutic targets and potential therapeutic molecules (RS-MESTD-Basic Research (BR or ON)-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
DOI: 10.1002/jcb.24154
ISSN: 0730-2312
PubMed: 22467095
WoS: 000305334900024
Scopus: 2-s2.0-84862517857
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VinčaTY - JOUR AU - Mancini, Manuela AU - Veljković, Nevena V. AU - Leo, Elisa AU - Aluigi, Michela AU - Borsi, Enrica AU - Galloni, Chiara AU - Iacobucci, Ilaria AU - Barbieri, Enza AU - Santucci, Maria Alessandra PY - 2012 UR - https://vinar.vin.bg.ac.rs/handle/123456789/4887 AB - 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. T2 - Journal of Cellular Biochemistry T1 - Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia VL - 113 IS - 8 SP - 2765 EP - 2774 DO - 10.1002/jcb.24154 ER -
@article{ author = "Mancini, Manuela and Veljković, Nevena V. and Leo, Elisa and Aluigi, Michela and Borsi, Enrica and Galloni, Chiara and Iacobucci, Ilaria and Barbieri, Enza and Santucci, Maria Alessandra", year = "2012", abstract = "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.", journal = "Journal of Cellular Biochemistry", title = "Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia", volume = "113", number = "8", pages = "2765-2774", doi = "10.1002/jcb.24154" }
Mancini, M., Veljković, N. V., Leo, E., Aluigi, M., Borsi, E., Galloni, C., Iacobucci, I., Barbieri, E.,& Santucci, M. A.. (2012). Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia. in Journal of Cellular Biochemistry, 113(8), 2765-2774. https://doi.org/10.1002/jcb.24154
Mancini M, Veljković NV, Leo E, Aluigi M, Borsi E, Galloni C, Iacobucci I, Barbieri E, Santucci MA. Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia. in Journal of Cellular Biochemistry. 2012;113(8):2765-2774. doi:10.1002/jcb.24154 .
Mancini, Manuela, Veljković, Nevena V., Leo, Elisa, Aluigi, Michela, Borsi, Enrica, Galloni, Chiara, Iacobucci, Ilaria, Barbieri, Enza, Santucci, Maria Alessandra, "Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia" in Journal of Cellular Biochemistry, 113, no. 8 (2012):2765-2774, https://doi.org/10.1002/jcb.24154 . .