A Remote GATA2 Hematopoietic Enhancer Drives Leukemogenesis in inv(3)(q21;q26) by Activating EVI1 Expression

• DOI: 10.1016/j.ccr.2014.02.008
• Publication Date: 2014-04-03T16:51:56Z
• Authors: Hiromi Yamazaki; Mikiko Suzuki; Akihito Otsuki; Ritsuko Shimizu; Emery H. Bresnick; James Douglas Engel; Masayuki Yamamoto
• Keywords: 0301 basic medicine; Cancer Research; Base Sequence; Mice, Transgenic; Cell Biology; Transfection; Proto-Oncogene Mas; MDS1 and EVI1 Complex Locus Protein; Translocation, Genetic; Hematopoiesis; DNA-Binding Proteins; GATA2 Transcription Factor; Leukemia, Myeloid, Acute; Mice; 03 medical and health sciences; Oncology; Chromosome Inversion; Proto-Oncogenes; Animals; Humans; Chromosomes, Human, Pair 3; Transgenes; Transcription Factors

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.