A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression.

Publication Type:

Journal Article

Authors:

Yamazaki, Hiromi; Suzuki, Mikiko; Otsuki, Akihito; Shimizu, Ritsuko; Bresnick, Emery H; Engel, James Douglas; Yamamoto, Masayuki

Source:

Cancer Cell, Volume 25, Issue 4, p.415-27 (2014)

Keywords:

Animals, asb, Base Sequence, Chromosome Inversion, Chromosomes, Human, Pair 3, DNA-Binding Proteins, GATA2 Transcription Factor, Hematopoiesis, Humans, Leukemia, Myeloid, Acute, MDS1 and EVI1 Complex Locus Protein, Mice, Mice, Transgenic, Proto-Oncogenes, Transcription Factors, Transfection, Transgenes, Translocation, Genetic

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.