Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis

Elife. 2015 Jul 20:4:e07839. doi: 10.7554/eLife.07839.

Abstract

Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS) and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germ line deletion of a 2-Mb interval of chromosome band 5A3 syntenic to a commonly deleted segment of human 7q22 and show that mutant hematopoietic cells exhibit cardinal features of MDS. Specifically, the long-term hematopoietic stem cell (HSC) compartment is expanded in 5A3(+/del) mice, and the distribution of myeloid progenitors is altered. 5A3(+/del) HSCs are defective for lymphoid repopulating potential and show a myeloid lineage output bias. These cell autonomous abnormalities are exacerbated by physiologic aging and upon serial transplantation. The 5A3 deletion partially rescues defective repopulation in Gata2 mutant mice. 5A3(+/del) hematopoietic cells exhibit decreased expression of oxidative phosphorylation genes, increased levels of reactive oxygen species, and perturbed oxygen consumption. These studies provide the first functional data linking 7q22 deletions to MDS pathogenesis.

Keywords: chromosome engineering; haploinsufficiency; hematopoietic stem cells; human biology; medicine; monosomy 7; mouse; myelodysplastic syndrome; oxidative phosphorylation.

Publication types

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

MeSH terms

  • Animals
  • Chromosomes, Human, Pair 7*
  • Disease Models, Animal
  • Genetic Loci*
  • Haploinsufficiency*
  • Humans
  • Mice, Inbred C57BL
  • Myelodysplastic Syndromes / genetics*
  • Oxidative Phosphorylation
  • Oxygen / metabolism
  • Reactive Oxygen Species / metabolism
  • Sequence Deletion

Substances

  • Reactive Oxygen Species
  • Oxygen