Document Detail


Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes.
MedLine Citation:
PMID:  21159644     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chimeric oncoproteins resulting from fusion of MLL to a wide variety of partnering proteins cause biologically distinctive and clinically aggressive acute leukemias. However, the mechanism of MLL-mediated leukemic transformation is not fully understood. Dot1, the only known histone H3 lysine 79 (H3K79) methyltransferase, has been shown to interact with multiple MLL fusion partners including AF9, ENL, AF10, and AF17. In this study, we utilize a conditional Dot1l deletion model to investigate the role of Dot1 in hematopoietic progenitor cell immortalization by MLL fusion proteins. Western blot and mass spectrometry show that Dot1-deficient cells are depleted of the global H3K79 methylation mark. We find that loss of Dot1 activity attenuates cell viability and colony formation potential of cells immortalized by MLL oncoproteins but not by the leukemic oncoprotein E2a-Pbx1. Although this effect is most pronounced for MLL-AF9, we find that Dot1 contributes to the viability of cells immortalized by other MLL oncoproteins that are not known to directly recruit Dot1. Cells immortalized by MLL fusions also show increased apoptosis, suggesting the involvement of Dot1 in survival pathways. In summary, our data point to a pivotal requirement for Dot1 in MLL fusion protein-mediated leukemogenesis and implicate Dot1 as a potential therapeutic target.
Authors:
Ming-Jin Chang; Hongyu Wu; Nicholas J Achille; Mary Rose Reisenauer; Chau-Wen Chou; Nancy J Zeleznik-Le; Charles S Hemenway; Wenzheng Zhang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-16     Completed Date:  2011-01-20     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10234-42     Citation Subset:  IM    
Copyright Information:
©2010 AACR.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / physiology
Cell Transformation, Neoplastic / genetics*,  metabolism
Hematopoietic Stem Cells / enzymology
Histones / metabolism
Leukemia, Experimental / enzymology,  genetics,  pathology
Lysine / metabolism
Methylation
Methyltransferases / antagonists & inhibitors,  deficiency,  genetics,  metabolism*
Mice
Myeloid-Lymphoid Leukemia Protein / genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
CA 098459/CA/NCI NIH HHS; CA 105049/CA/NCI NIH HHS; DK 080236/DK/NIDDK NIH HHS; P01 CA105049-04/CA/NCI NIH HHS; P01 CA105049-05/CA/NCI NIH HHS; R01 CA098459/CA/NCI NIH HHS; R01 CA098459-06/CA/NCI NIH HHS; R01 DK080236/DK/NIDDK NIH HHS; R01 DK080236-02/DK/NIDDK NIH HHS; R01 DK080236-03/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Histones; 149025-06-9/Myeloid-Lymphoid Leukemia Protein; EC 2.1.1.-/Dot1l protein, mouse; EC 2.1.1.-/Methyltransferases; K3Z4F929H6/Lysine
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