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Cancer Cell. 2014 Apr 14;25(4):415-27. doi: 10.1016/j.ccr.2014.02.008. Epub 2014 Apr 3.

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

Author information

1
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
2
Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
3
Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
4
UW-Madison Blood Research Program, Carbone Cancer Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
5
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
6
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Tohoku Medical Megabank, Tohoku University, Sendai 980-8573, Japan. Electronic address: masiyamamoto@med.tohoku.ac.jp.

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.

PMID:
24703906
PMCID:
PMC4012341
DOI:
10.1016/j.ccr.2014.02.008
[Indexed for MEDLINE]
Free PMC Article

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