PMID- 21159644
OWN - NLM
STAT- MEDLINE
DCOM- 20110120
LR  - 20211020
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 70
IP  - 24
DP  - 2010 Dec 15
TI  - Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by 
      MLL oncogenes.
PG  - 10234-42
LID - 10.1158/0008-5472.CAN-10-3294 [doi]
AB  - 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.
CI  - (c)2010 AACR.
FAU - Chang, Ming-Jin
AU  - Chang MJ
AD  - Department of Biochemistry, Tulane University, New Orleans, Louisiana, USA.
FAU - Wu, Hongyu
AU  - Wu H
FAU - Achille, Nicholas J
AU  - Achille NJ
FAU - Reisenauer, Mary Rose
AU  - Reisenauer MR
FAU - Chou, Chau-Wen
AU  - Chou CW
FAU - Zeleznik-Le, Nancy J
AU  - Zeleznik-Le NJ
FAU - Hemenway, Charles S
AU  - Hemenway CS
FAU - Zhang, Wenzheng
AU  - Zhang W
LA  - eng
GR  - P01 CA105049-04/CA/NCI NIH HHS/United States
GR  - R01 DK080236/DK/NIDDK NIH HHS/United States
GR  - R01 CA098459-06/CA/NCI NIH HHS/United States
GR  - CA 105049/CA/NCI NIH HHS/United States
GR  - CA 098459/CA/NCI NIH HHS/United States
GR  - R01 CA098459/CA/NCI NIH HHS/United States
GR  - P01 CA105049/CA/NCI NIH HHS/United States
GR  - R01 DK080236-03/DK/NIDDK NIH HHS/United States
GR  - P01 CA105049-05/CA/NCI NIH HHS/United States
GR  - R01 DK080236-02/DK/NIDDK NIH HHS/United States
GR  - DK 080236/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Histones)
RN  - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
RN  - EC 2.1.1.- (Dot1l protein, mouse)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Animals
MH  - Apoptosis/physiology
MH  - Cell Transformation, Neoplastic/*genetics/metabolism
MH  - Hematopoietic Stem Cells/enzymology
MH  - Histone-Lysine N-Methyltransferase
MH  - Histones/metabolism
MH  - Leukemia, Experimental/enzymology/genetics/pathology
MH  - Lysine/metabolism
MH  - Methylation
MH  - Methyltransferases/antagonists & inhibitors/deficiency/genetics/*metabolism
MH  - Mice
MH  - Myeloid-Lymphoid Leukemia Protein/*genetics/metabolism
PMC - PMC3040779
MID - NIHMS263101
COIS- Disclosure of Potential Conflicts of Interest The authors have no conflicts of 
      interest to disclose
EDAT- 2010/12/17 06:00
MHDA- 2011/01/21 06:00
PMCR- 2011/12/15
CRDT- 2010/12/17 06:00
PHST- 2010/12/17 06:00 [entrez]
PHST- 2010/12/17 06:00 [pubmed]
PHST- 2011/01/21 06:00 [medline]
PHST- 2011/12/15 00:00 [pmc-release]
AID - 70/24/10234 [pii]
AID - 10.1158/0008-5472.CAN-10-3294 [doi]
PST - ppublish
SO  - Cancer Res. 2010 Dec 15;70(24):10234-42. doi: 10.1158/0008-5472.CAN-10-3294.