Abstract
Chromosomal inversion between 3q21 and 3q26 results in high-risk acute myeloid leukemia (AML). In this study, we identified a mechanism whereby a GATA2 distal hematopoietic enhancer (G2DHE or -77-kb enhancer) is brought into close proximity to the EVI1 gene in inv(3)(q21;q26) inversions, leading to leukemogenesis. We examined the contribution of G2DHE to leukemogenesis by creating a bacterial artificial chromosome (BAC) transgenic model that recapitulates the inv(3)(q21;q26) allele. Transgenic mice harboring a linked BAC developed leukemia accompanied by EVI1 overexpression-neoplasia that was not detected in mice bearing the same transgene but that was missing the GATA2 enhancer. These results establish the mechanistic basis underlying the pathogenesis of a severe form of leukemia through aberrant expression of the EVI1 proto-oncogene.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Chromosome Inversion*
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Chromosomes, Human, Pair 3*
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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GATA2 Transcription Factor / genetics*
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GATA2 Transcription Factor / metabolism
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Hematopoiesis / genetics*
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Humans
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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, Transgenic
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Proto-Oncogene Mas
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Proto-Oncogenes / genetics
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
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Transgenes
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Translocation, Genetic
Substances
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DNA-Binding Proteins
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GATA2 Transcription Factor
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GATA2 protein, human
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MAS1 protein, human
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MDS1 and EVI1 Complex Locus Protein
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MECOM protein, human
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Proto-Oncogene Mas
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Transcription Factors