title: Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins.
abstract: 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.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Yoshimi
authors.forename: Susumu
authors.initials: S
authors.lastname: Goyama
authors.forename: Naoko
authors.initials: N
authors.lastname: Watanabe-Okochi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yoshiki
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nannya
authors.forename: Eriko
authors.initials: E
authors.lastname: Nitta
authors.forename: Shunya
authors.initials: S
authors.lastname: Arai
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sato
authors.forename: Munetake
authors.initials: M
authors.lastname: Shimabe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imai
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011519:Proto-Oncogenes / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D063146:Polycomb-Group Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C063575:MECOM protein, human; C546842:MTOR protein, human