Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS), and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germline 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 (MP) 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.
Animal experimentation: Study mice were housed in a specific pathogen-free facility at the University of California San Francisco, and all animal experiments were conducted in strict accordance with the protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the University of California, San Francisco (Approval number: AN091877-03).
- Chi Van Dang, University of Pennsylvania, United States
© 2015, Wong et al.
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