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Nat Biotechnol. 2015 Jun;33(6):646-55. doi: 10.1038/nbt.3178. Epub 2015 Mar 23.

Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells.

Author information

1
1] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
1] Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA. [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
3
Genomics Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
4
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA.
5
1] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. [2] Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
6
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
7
1] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. [2] Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
8
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
9
Developmental Biology Program, Sloan-Kettering Institute, New York, New York, USA.
10
1] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. [2] Department of Pathology, University of Washington, Seattle, Washington, USA. [3] Center for Cardiovascular Biology, University of Washington, Seattle, Washington, USA. [4] Department of Bioengineering University of Washington, Seattle, Washington, USA. [5] Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA.
11
MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
12
1] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [4] Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA. [5] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. [6] Department of Pathology, University of Washington, Seattle, Washington, USA. [7] Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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.

PMID:
25798938
PMCID:
PMC4464949
DOI:
10.1038/nbt.3178
[Indexed for MEDLINE]
Free PMC Article

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