A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression.
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.
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Hiromi
H
Yamazaki
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.
Mikiko
M
Suzuki
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Akihito
A
Otsuki
Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Ritsuko
R
Shimizu
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.
Emery H
EH
Bresnick
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
James Douglas
JD
Engel
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.
Masayuki
M
Yamamoto
D000818:Animals; D001483:Base Sequence; D007446:Chromosome Inversion; D002893:Chromosomes, Human, Pair 3; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D019076:Transgenes; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C000715470:MAS1 protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors