dissecting the contributions of cooperating gene mutations to cancer phenotypes and drug responses with patient-derived ipscs

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ID: 160590
2018
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Ranked #23 of 101 articles by views in nature reviews gastroenterology & hepatology

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Abstract
Summary: Connecting specific cancer genotypes with phenotypes and drug responses constitutes the central premise of precision oncology but is hindered by the genetic complexity and heterogeneity of primary cancer cells. Here, we use patient-derived induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 genome editing to dissect the individual contributions of two recurrent genetic lesions, the splicing factor SRSF2 P95L mutation and the chromosome 7q deletion, to the development of myeloid malignancy. Using a comprehensive panel of isogenic iPSCs—with none, one, or both genetic lesions—we characterize their relative phenotypic contributions and identify drug sensitivities specific to each one through a candidate drug approach and an unbiased large-scale small-molecule screen. To facilitate drug testing and discovery, we also derive SRSF2-mutant and isogenic normal expandable hematopoietic progenitor cells. We thus describe here an approach to dissect the individual effects of two cooperating mutations to clinically relevant features of malignant diseases. : Papapetrou and colleagues develop a comprehensive panel of isogenic iPSC lines with SRSF2 P95L mutation and chr7q deletion. They use these cells to identify cellular phenotypes contributed by each genetic lesion and therapeutic vulnerabilities specific to each one and develop expandable hematopoietic progenitor cell lines to facilitate drug discovery. Keywords: induced pluripotent stem cells, myelodysplastic syndrome, CRISPR/Cas9, gene editing, mutational cooperation, splicing factor mutations, spliceosomal mutations, SRSF2, chr7q deletion
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chang2018stemdissecting Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Chan-Jung Chang;Andriana G. Kotini;Malgorzata Olszewska;Maria Georgomanoli;Julie Teruya-Feldstein;Henrik Sperber;Roberto Sanchez;Robert DeVita;Timothy J. Martins;Omar Abdel-Wahab;Robert K. Bradley;Eirini P. Papapetrou
Journal nature reviews gastroenterology & hepatology
Year 2018
DOI
DOI not found
URL
http://www.sciencedirect.com/science/article/pii/S2213671118301474
Keywords
medicine (general)biology (general)

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