Document Detail


Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l.
MedLine Citation:
PMID:  23138183     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The t(10;11)(p12;q23) translocation and the t(10;11)(p12;q14) translocation, which encode the MLL (mixed lineage leukemia)-AF10 and CALM (clathrin assembly lymphoid myeloid leukemia)-AF10 fusion oncoproteins, respectively, are two recurrent chromosomal rearrangements observed in patients with acute myeloid leukemia and acute lymphoblastic leukemia. Here, we demonstrate that MLL-AF10 and CALM-AF10-mediated transformation is dependent on the H3K79 methyltransferase Dot1l using genetic and pharmacological approaches in mouse models. Targeted disruption of Dot1l using a conditional knockout mouse model abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL-AF10 or CALM-AF10 leukemia. The treatment of MLL-AF10 and CALM-AF10 transformed cells with EPZ004777, a specific small-molecule inhibitor of Dot1l, suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1, and selectively impaired proliferation of MLL-AF10 and CALM-AF10 transformed cells. Pretreatment with EPZ004777 profoundly decreased the in vivo spleen-colony-forming ability of MLL-AF10 or CALM-AF10 transformed bone marrow cells. These results show that patients with leukemia-bearing chromosomal translocations that involve the AF10 gene may benefit from small-molecule therapeutics that inhibit H3K79 methylation.
Authors:
L Chen; A J Deshpande; D Banka; K M Bernt; S Dias; C Buske; E J Olhava; S R Daigle; V M Richon; R M Pollock; S A Armstrong
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-09
Journal Detail:
Title:  Leukemia     Volume:  27     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-11     Completed Date:  2013-06-04     Revised Date:  2014-04-17    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  813-22     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Blotting, Western
Cell Cycle
Cell Proliferation
Enzyme Inhibitors / pharmacology*
Fluorescent Antibody Technique
Gene Silencing*
Humans
Methyltransferases / antagonists & inhibitors*
Mice
Mice, Mutant Strains
Myeloid-Lymphoid Leukemia Protein / genetics*
Oncogene Proteins, Fusion / genetics*
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
P30 DK049216/DK/NIDDK NIH HHS; R01 CA140575/CA/NCI NIH HHS; R01CA140575/CA/NCI NIH HHS; U01 CA105423/CA/NCI NIH HHS; U01CA105423/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/AF10-CALM fusion protein, human; 0/Enzyme Inhibitors; 0/MLL-AF10 fusion protein, human; 0/Oncogene Proteins, Fusion; 149025-06-9/Myeloid-Lymphoid Leukemia Protein; EC 2.1.1.-/Methyltransferases
Comments/Corrections

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