PMID- 21289308
OWN - NLM
STAT- MEDLINE
DCOM- 20110602
LR  - 20211203
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 117
IP  - 13
DP  - 2011 Mar 31
TI  - Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with 
      polycomb proteins.
PG  - 3617-28
LID - 10.1182/blood-2009-12-261602 [doi]
AB  - Evi1 (ecotropic viral integration site 1) is essential for proliferation of 
      hematopoietic stem cells and implicated in the development of myeloid disorders. 
      Particularly, high Evi1 expression defines one of the largest clusters in acute 
      myeloid leukemia and is significantly associated with extremely poor prognosis. 
      However, mechanistic basis of Evi1-mediated leukemogenesis has not been fully 
      elucidated. Here, we show that Evi1 directly represses phosphatase and tensin 
      homologue deleted on chromosome 10 (PTEN) transcription in the murine bone 
      marrow, which leads to activation of AKT/mammalian target of rapamycin (mTOR) 
      signaling. In a murine bone marrow transplantation model, Evi1 leukemia showed 
      modestly increased sensitivity to an mTOR inhibitor rapamycin. Furthermore, we 
      found that Evi1 binds to several polycomb group proteins and recruits polycomb 
      repressive complexes for PTEN down-regulation, which shows a novel epigenetic 
      mechanism of AKT/mTOR activation in leukemia. Expression analyses and ChIPassays 
      with human samples indicate that our findings in mice models are recapitulated in 
      human leukemic cells. Dependence of Evi1-expressing leukemic cells on AKT/mTOR 
      signaling provides the first example of targeted therapeutic modalities that 
      suppress the leukemogenic activity of Evi1. The PTEN/AKT/mTOR signaling pathway 
      and the Evi1-polycomb interaction can be promising therapeutic targets for 
      leukemia with activated Evi1.
FAU - Yoshimi, Akihide
AU  - Yoshimi A
AD  - Department of Hematology and Oncology, Graduate School of Medicine, University of 
      Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
FAU - Goyama, Susumu
AU  - Goyama S
FAU - Watanabe-Okochi, Naoko
AU  - Watanabe-Okochi N
FAU - Yoshiki, Yumiko
AU  - Yoshiki Y
FAU - Nannya, Yasuhito
AU  - Nannya Y
FAU - Nitta, Eriko
AU  - Nitta E
FAU - Arai, Shunya
AU  - Arai S
FAU - Sato, Tomohiko
AU  - Sato T
FAU - Shimabe, Munetake
AU  - Shimabe M
FAU - Nakagawa, Masahiro
AU  - Nakagawa M
FAU - Imai, Yoichi
AU  - Imai Y
FAU - Kitamura, Toshio
AU  - Kitamura T
FAU - Kurokawa, Mineo
AU  - Kurokawa M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110202
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (MDS1 and EVI1 Complex Locus Protein)
RN  - 0 (MECOM protein, human)
RN  - 0 (Polycomb-Group Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/metabolism/*physiology
MH  - Down-Regulation/genetics
MH  - Female
MH  - Gene Expression Regulation, Leukemic
MH  - Humans
MH  - Leukemia/genetics/metabolism/pathology
MH  - MDS1 and EVI1 Complex Locus Protein
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Middle Aged
MH  - Models, Biological
MH  - PTEN Phosphohydrolase/*genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Polycomb-Group Proteins
MH  - Protein Binding
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Proto-Oncogenes/*physiology
MH  - Repressor Proteins/*metabolism
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transcription Factors/metabolism/*physiology
MH  - Young Adult
EDAT- 2011/02/04 06:00
MHDA- 2011/06/03 06:00
CRDT- 2011/02/04 06:00
PHST- 2011/02/04 06:00 [entrez]
PHST- 2011/02/04 06:00 [pubmed]
PHST- 2011/06/03 06:00 [medline]
AID - S0006-4971(20)49401-7 [pii]
AID - 10.1182/blood-2009-12-261602 [doi]
PST - ppublish
SO  - Blood. 2011 Mar 31;117(13):3617-28. doi: 10.1182/blood-2009-12-261602. Epub 2011 
      Feb 2.