Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells Journal Article
| Authors: | Kotini, A. G.; Chang, C. J.; Boussaad, I.; Delrow, J. J.; Dolezal, E. K.; Nagulapally, A. B.; Perna, F.; Fishbein, G. A.; Klimek, V. M.; Hawkins, R. D.; Huangfu, D.; Murry, C. E.; Graubert, T.; Nimer, S. D.; Papapetrou, E. P. |
| Article Title: | Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells |
| 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. © 2015 Nature America, Inc. All rights reserved. |
| Keywords: | controlled study; human cell; gene deletion; phenotype; cytology; mus; disease association; genes; cytogenetics; cell differentiation; myelodysplastic syndrome; genetic engineering; hematopoietic cell; stem cells; hemizygosity; pluripotent stem cell; chromosome deletion; karyotyping; chromosomes; myelodysplastic syndromes; nuclear reprogramming; induced pluripotent stem cells; chromosome 7q; cells; haploinsufficiency; cellular reprogramming; cell engineering; human; priority journal; article; genome engineering; mobile security; chromosomal deletions; disease phenotypes; functional mapping; human-induced pluripotent stem cells |
| Journal Title: | Nature Biotechnology |
| Volume: | 33 |
| Issue: | 6 |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-06-01 |
| Start Page: | 646 |
| End Page: | 655 |
| Language: | English |
| DOI: | 10.1038/nbt.3178 |
| PROVIDER: | scopus |
| PMCID: | PMC4464949 |
| PUBMED: | 25798938 |
| DOI/URL: | |
| Notes: | Export Date: 2 July 2015 -- Source: Scopus |
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