Cytoplasmatic compartmentalization by Bcr-Abl promotes TET2 loss-of-function in chronic myeloid leukemia

被引:17
作者
Mancini, Manuela [1 ]
Veljkovic, Nevena [2 ]
Leo, Elisa [1 ]
Aluigi, Michela [1 ]
Borsi, Enrica [1 ]
Galloni, Chiara [1 ]
Iacobucci, Ilaria [1 ]
Barbieri, Enza [3 ]
Santucci, Maria Alessandra [1 ]
机构
[1] Univ Bologna, Dipartimento Ematol & Sci Oncol Lorenzo & Ariosto, Sch Med, I-40138 Bologna, Italy
[2] Univ Belgrade, Ctr Multidisciplinary Res, Inst Nucl Sci, Belgrade, Serbia
[3] Univ Bologna, Dipartimento Sci Radiol & Istopatol, Ist Radioterapia Luigi Galvani, Sch Med, I-40138 Bologna, Italy
关键词
CHRONIC MYELOID LEUKEMIA; Bcr-Abl; TET2; BIM; FoxO3a; EPIGENETIC MODIFICATIONS; ACUTE LYMPHOBLASTIC-LEUKEMIA; HEMATOPOIETIC STEM-CELLS; SELF-RENEWAL; MLL; BIM; PROTEIN; DNA; 5-METHYLCYTOSINE; INHIBITOR; HYDROXYLATION;
D O I
10.1002/jcb.24154
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2765 / 2774
页数:10
相关论文
共 48 条
[1]   Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition [J].
Bachmann, Petra S. ;
Piazza, Rocco G. ;
Janes, Mary E. ;
Wong, Nicholas C. ;
Davies, Carwyn ;
Mogavero, Angela ;
Bhadri, Vivek A. ;
Szymanska, Barbara ;
Geninson, Greta ;
Magistroni, Vera ;
Cazzaniga, Giovanni ;
Biondi, Andrea ;
Miranda-Saavedra, Diego ;
Goettgens, Berthold ;
Saffery, Richard ;
Craig, Jeffrey M. ;
Marshall, Glenn M. ;
Gambacorti-Passerini, Carlo ;
Pimanda, John E. ;
Lock, Richard B. .
BLOOD, 2010, 116 (16) :3013-3022
[2]   Aberrant Epigenetic Landscape in Cancer: How Cellular Identity Goes Awry [J].
Berdasco, Maria ;
Esteller, Manel .
DEVELOPMENTAL CELL, 2010, 19 (05) :698-711
[3]   Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].
Brunet, A ;
Bonni, A ;
Zigmond, MJ ;
Lin, MZ ;
Juo, P ;
Hu, LS ;
Anderson, MJ ;
Arden, KC ;
Blenis, J ;
Greenberg, ME .
CELL, 1999, 96 (06) :857-868
[4]   P210 Bcr-abl tyrosine kinase interaction with histone deacetylase 1 modifies histone H4 acetylation and chromatin structure of chronic myeloid leukaemia haematopoietic progenitors [J].
Brusa, G ;
Zuffa, E ;
Mancini, M ;
Benvenuti, M ;
Calonghi, N ;
Barbieri, E ;
Santucci, MA .
BRITISH JOURNAL OF HAEMATOLOGY, 2006, 132 (03) :359-369
[5]   The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group [J].
Burmeister, Thomas ;
Meyer, Claus ;
Schwartz, Stefan ;
Hofmann, Julia ;
Molkentin, Mara ;
Kowarz, Eric ;
Schneider, Bjoern ;
Raff, Thorsten ;
Reinhardt, Richard ;
Goekbuget, Nicola ;
Hoelzer, Dieter ;
Thiel, Eckhard ;
Marschalek, Rolf .
BLOOD, 2009, 113 (17) :4011-4015
[6]   Acetylation of FOXO3a transcription factor in response to imatinib of chronic myeloid leukemia [J].
Corrado, P. ;
Mancini, M. ;
Brusa, G. ;
Petta, S. ;
Martinelli, G. ;
Barbieri, E. ;
Santucci, M. A. .
LEUKEMIA, 2009, 23 (02) :405-406
[7]   Advances in DNA methylation: 5-hydroxymethylcytosine revisited [J].
Dahl, Christina ;
Gronbaek, Kirsten ;
Guldberg, Per .
CLINICA CHIMICA ACTA, 2011, 412 (11-12) :831-836
[8]   IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms [J].
De Bruyne, Elke ;
Bos, Tomas J. ;
Schuit, Frans ;
Van Valckenborgh, Els ;
Menu, Eline ;
Thorrez, Lieven ;
Atadja, Peter ;
Jernberg-Wiklund, Helena ;
Vanderkerken, Karin .
BLOOD, 2010, 115 (12) :2430-2440
[9]   Targeting 14-3-3 sensitizes native and mutant BCR-ABL to inhibition with U0126, rapamycin and Bcl-2 inhibitor GX15-070 [J].
Dong, S. ;
Kang, S. ;
Lonial, S. ;
Khoury, H. J. ;
Viallet, J. ;
Chen, J. .
LEUKEMIA, 2008, 22 (03) :572-577
[10]   Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells [J].
Essafi, A ;
de Mattos, SF ;
Hassen, YAM ;
Soeiro, I ;
Mufti, GJ ;
Thomas, NSB ;
Medema, RH ;
Lam, EWF .
ONCOGENE, 2005, 24 (14) :2317-2329