title: EVI-1 modulates leukemogenic potential and apoptosis sensitivity in human acute lymphoblastic leukemia.
abstract: The transcriptional regulator ecotropic viral integration site-1 (EVI-1) has mainly been studied for its role in myeloid malignancies, in which high EVI-1 levels are associated with particularly aggressive disease. The role of EVI-1 in lymphoid cells, however, is largely unknown. Here we show that EVI-1 is indeed expressed in lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and a subset of chronic lymphocytic leukemia. Expression data from pediatric ALL further suggest that high EVI-1 levels are associated with poor prognosis. Suppression of EVI-1 expression by RNA interference reduces cell growth and enhances apoptosis sensitivity in response to various stimuli in lymphoblastic leukemia cells. At the molecular level, EVI-1 modulates expression of several apoptosis-related genes (such as BCL2, BCL-x, XIAP, NOXA, PUMA, TRAIL-R1). Furthermore, EVI-1 knockdown strongly impairs in vivo engraftment of lymphoblastic leukemia cells upon transplantation in immune-permissive NOD/SCID/IL2Rγ(null) mice, conferring a survival benefit when compared with mice transplanted with control cells. Thus, our data show that EVI-1 is expressed not only in myeloid but also in lymphoid leukemias, and contributes to the leukemogenic potential and apoptosis resistance of ALL cells.
authors: Department of Hematology and Oncology, University of Tuebingen Medical Center II, Tuebingen, Germany.
authors: M
authors: M
authors: Konantz
authors: M C
authors: MC
authors: André
authors: M
authors: M
authors: Ebinger
authors: M
authors: M
authors: Grauer
authors: H
authors: H
authors: Wang
authors: S
authors: S
authors: Grzywna
authors: O C
authors: OC
authors: Rothfuss
authors: S
authors: S
authors: Lehle
authors: O S
authors: OS
authors: Kustikova
authors: H R
authors: HR
authors: Salih
authors: R
authors: R
authors: Handgretinger
authors: F
authors: F
authors: Fend
authors: C
authors: C
authors: Baum
authors: L
authors: L
authors: Kanz
authors: L
authors: L
authors: Quintanilla-Martinez
authors: K
authors: K
authors: Schulze-Osthoff
authors: F
authors: F
authors: Essmann
authors: C
authors: C
authors: Lengerke
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D002648:Child; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011519:Proto-Oncogenes / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors