Abstract
Chromosomal deletions associated with human diseases, such as cancer, are common, but synteny issues complicate modeling of these deletions in mice. We use cellular reprogramming and genome engineering to functionally dissect the loss of chromosome 7q (del(7q)), a somatic cytogenetic abnormality present in myelodysplastic syndromes (MDS). We derive del(7q)- and isogenic karyotypically normal induced pluripotent stem cells (iPSCs) from hematopoietic cells of MDS patients and show that the del(7q) iPSCs recapitulate disease-associated phenotypes, including impaired hematopoietic differentiation. These disease phenotypes are rescued by spontaneous dosage correction and can be reproduced in karyotypically normal cells by engineering hemizygosity of defined chr7q segments in a 20-Mb region. We use a phenotype-rescue screen to identify candidate haploinsufficient genes that might mediate the del(7q)- hematopoietic defect. Our approach highlights the utility of human iPSCs both for functional mapping of disease-associated large-scale chromosomal deletions and for discovery of haploinsufficient genes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 646-655 |
| Number of pages | 10 |
| Journal | Nature Biotechnology |
| Volume | 33 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 11 2015 |
Fingerprint
ASJC Scopus subject areas
- Applied Microbiology and Biotechnology
- Biotechnology
- Molecular Medicine
- Bioengineering
- Biomedical Engineering
Cite this
Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. / Kotini, Andriana G.; Chang, Chan Jung; Boussaad, Ibrahim; Delrow, Jeffrey J.; Dolezal, Emily K.; Nagulapally, Abhinav B.; Perna, Fabiana; Fishbein, Gregory A.; Klimek, Virginia M.; Hawkins, R. David; Huangfu, Danwei; Murry, Charles E.; Graubert, Timothy; Nimer, Stephen D; Papapetrou, Eirini P.
In: Nature Biotechnology, Vol. 33, No. 6, 11.06.2015, p. 646-655.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells
AU - Kotini, Andriana G.
AU - Chang, Chan Jung
AU - Boussaad, Ibrahim
AU - Delrow, Jeffrey J.
AU - Dolezal, Emily K.
AU - Nagulapally, Abhinav B.
AU - Perna, Fabiana
AU - Fishbein, Gregory A.
AU - Klimek, Virginia M.
AU - Hawkins, R. David
AU - Huangfu, Danwei
AU - Murry, Charles E.
AU - Graubert, Timothy
AU - Nimer, Stephen D
AU - Papapetrou, Eirini P.
PY - 2015/6/11
Y1 - 2015/6/11
N2 - Chromosomal deletions associated with human diseases, such as cancer, are common, but synteny issues complicate modeling of these deletions in mice. We use cellular reprogramming and genome engineering to functionally dissect the loss of chromosome 7q (del(7q)), a somatic cytogenetic abnormality present in myelodysplastic syndromes (MDS). We derive del(7q)- and isogenic karyotypically normal induced pluripotent stem cells (iPSCs) from hematopoietic cells of MDS patients and show that the del(7q) iPSCs recapitulate disease-associated phenotypes, including impaired hematopoietic differentiation. These disease phenotypes are rescued by spontaneous dosage correction and can be reproduced in karyotypically normal cells by engineering hemizygosity of defined chr7q segments in a 20-Mb region. We use a phenotype-rescue screen to identify candidate haploinsufficient genes that might mediate the del(7q)- hematopoietic defect. Our approach highlights the utility of human iPSCs both for functional mapping of disease-associated large-scale chromosomal deletions and for discovery of haploinsufficient genes.
AB - Chromosomal deletions associated with human diseases, such as cancer, are common, but synteny issues complicate modeling of these deletions in mice. We use cellular reprogramming and genome engineering to functionally dissect the loss of chromosome 7q (del(7q)), a somatic cytogenetic abnormality present in myelodysplastic syndromes (MDS). We derive del(7q)- and isogenic karyotypically normal induced pluripotent stem cells (iPSCs) from hematopoietic cells of MDS patients and show that the del(7q) iPSCs recapitulate disease-associated phenotypes, including impaired hematopoietic differentiation. These disease phenotypes are rescued by spontaneous dosage correction and can be reproduced in karyotypically normal cells by engineering hemizygosity of defined chr7q segments in a 20-Mb region. We use a phenotype-rescue screen to identify candidate haploinsufficient genes that might mediate the del(7q)- hematopoietic defect. Our approach highlights the utility of human iPSCs both for functional mapping of disease-associated large-scale chromosomal deletions and for discovery of haploinsufficient genes.
UR - http://www.scopus.com/inward/record.url?scp=84930943281&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930943281&partnerID=8YFLogxK
U2 - 10.1038/nbt.3178
DO - 10.1038/nbt.3178
M3 - Article
C2 - 25798938
AN - SCOPUS:84930943281
VL - 33
SP - 646
EP - 655
JO - Nature Biotechnology
JF - Nature Biotechnology
SN - 1087-0156
IS - 6
ER -