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Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells
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 pres...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464949/ https://www.ncbi.nlm.nih.gov/pubmed/25798938 http://dx.doi.org/10.1038/nbt.3178 |
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author | 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 |
author_facet | 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 |
author_sort | Kotini, Andriana G |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4464949 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-44649492015-12-01 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 Nat Biotechnol Article 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. 2015-03-23 2015-06 /pmc/articles/PMC4464949/ /pubmed/25798938 http://dx.doi.org/10.1038/nbt.3178 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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 Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells |
title | Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells |
title_full | Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells |
title_fullStr | Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells |
title_full_unstemmed | Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells |
title_short | Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells |
title_sort | functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464949/ https://www.ncbi.nlm.nih.gov/pubmed/25798938 http://dx.doi.org/10.1038/nbt.3178 |
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