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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • DNA-Binding Proteins
  • GATA2 Transcription Factor
  • GATA2 protein, human
  • MDS1 and EVI1 Complex Locus Protein
  • MECOM protein, human
  • Transcription Factors