Image by James Thomson
A new study has improved researchers’ understanding of a genetic defect associated with myelodysplastic syndromes (MDS), and the team hopes this will ultimately help us correct the defect in patients.
The researchers used induced pluripotent stem cells (iPSCs) to study del(7q), a chromosomal abnormality found in patients with MDS.
This provided the team with new insight into how the deletion contributes to MDS development.
Steven D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described this work in Nature Biotechnology.
To determine how del(7q) contributes to MDS development, the researchers isolated hematopoietic cells from a patient with del(7q) and reprogrammed them into iPSCs. These iPSCs recapitulated MDS-associated phenotypes, including impaired hematopoietic differentiation.
The researchers also showed that, by engineering heterozygous chromosome 7q loss, they could recapitulate in normal iPSCs the characteristics they observed in the del(7q) iPSCs.
So the team was not surprised to find that disease phenotypes were rescued when del(7q) iPSC lines acquired a duplicate copy of chromosome 7q material.
The researchers also found that hemizygosity of chromosome 7q reduced the expression of many genes in the chromosome7q-deleted region. But gene expression was restored upon chromosome 7q dosage correction.
“[W]e were able to pinpoint a region on chromosome 7 that is critical and were able to identify candidate genes residing there that may cause this disease,” said study author Eirini Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
Focusing on hits residing in this region, 7q32.3–7q36.1, the researchers found 10 genes that were enriched (by >1.5-fold) recurrently.
Further investigation confirmed that 4 of these genes—HIPK2, ATP6V0E2, LUC7L2, and EZH2—could partially rescue the emergence of CD45+ hematopoietic progenitors when overexpressed in del(7q) iPSCs.
The researchers conducted additional experiments focusing on EZH2 alone and found that haploinsufficiency of EZH2 decreases cells’ hematopoietic potential.
But it seems the hematopoietic defects caused by chromosome 7q hemizygosity are mediated through the haploinsufficiency of EZH2 in combination with 1 or more additional genes, which might include LUC7L2, HIPK2, ATP6V0E2, and/or other genes.
