title: Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia.
abstract: The loss-of-function of ten-eleven-translocation (TET) 2, a Fe(2+) -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.
authors.affiliation: Dipartimento di Ematologia e Scienze Oncologiche Lorenzo e Ariosto Seràgnoli, University of Bologna-Medical School, Bologna, Italy. mancini_manu@yahoo.com
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.forename: Nevena
authors.initials: N
authors.lastname: Veljkovic
authors.forename: Elisa
authors.initials: E
authors.lastname: Leo
authors.forename: Michela
authors.initials: M
authors.lastname: Aluigi
authors.forename: Enrica
authors.initials: E
authors.lastname: Borsi
authors.forename: Chiara
authors.initials: C
authors.lastname: Galloni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Enza
authors.initials: E
authors.lastname: Barbieri
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D044127:Epigenesis, Genetic / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D016044:Fusion Proteins, bcr-abl