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

Andriana G. Kotini, Chan Jung Chang, Ibrahim Boussaad, Jeffrey J. Delrow, Emily K. Dolezal, Abhinav B. Nagulapally, Fabiana Perna, Gregory A. Fishbein, Virginia M. Klimek, R. David Hawkins, Danwei Huangfu, Charles E. Murry, Timothy Graubert, Stephen D Nimer, Eirini P. Papapetrou

Research output: Contribution to journalArticle

71 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)646-655
Number of pages10
JournalNature Biotechnology
Volume33
Issue number6
DOIs
StatePublished - Jun 11 2015

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Induced Pluripotent Stem Cells
Functional analysis
Myelodysplastic Syndromes
Chromosomes
Stem cells
Genes
Phenotype
Cell Engineering
Synteny
Genetic Association Studies
Chromosome Aberrations
Genome
Defects
Neoplasms

ASJC Scopus subject areas

  • Applied Microbiology and Biotechnology
  • Biotechnology
  • Molecular Medicine
  • Bioengineering
  • Biomedical Engineering

Cite this

Kotini, A. G., Chang, C. J., Boussaad, I., Delrow, J. J., Dolezal, E. K., Nagulapally, A. B., ... Papapetrou, E. P. (2015). Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nature Biotechnology, 33(6), 646-655. https://doi.org/10.1038/nbt.3178

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 journalArticle

Kotini, AG, Chang, CJ, Boussaad, I, Delrow, JJ, Dolezal, EK, Nagulapally, AB, Perna, F, Fishbein, GA, Klimek, VM, Hawkins, RD, Huangfu, D, Murry, CE, Graubert, T, Nimer, SD & Papapetrou, EP 2015, 'Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells', Nature Biotechnology, vol. 33, no. 6, pp. 646-655. https://doi.org/10.1038/nbt.3178
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. In: Nature Biotechnology. 2015 ; Vol. 33, No. 6. pp. 646-655.
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