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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Apoptosis*
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Blotting, Western
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Case-Control Studies
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Cell Cycle
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Cell Proliferation
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Child
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Fluorescent Antibody Technique
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Humans
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Interleukin Receptor Common gamma Subunit / physiology
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology*
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MDS1 and EVI1 Complex Locus Protein
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Proto-Oncogenes / genetics
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RNA, Small Interfering / genetics
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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Il2rg protein, mouse
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Interleukin Receptor Common gamma Subunit
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MDS1 and EVI1 Complex Locus Protein
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MECOM protein, human
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RNA, Small Interfering
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Transcription Factors