Dissecting the Contributions of Cooperating Gene Mutations to Cancer Phenotypes and Drug Responses with Patient-Derived iPSCs
| Autor: | Robert K. Bradley, Eirini P. Papapetrou, Roberto Sanchez, Robert J. DeVita, Julie Teruya-Feldstein, Timothy J. Martins, Maria Georgomanoli, Andriana G. Kotini, Henrik Sperber, Chan Jung Chang, Malgorzata Olszewska, Omar Abdel-Wahab |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
induced pluripotent stem cells Antineoplastic Agents Computational biology Gene mutation Biology medicine.disease_cause Biochemistry Article Small Molecule Libraries 03 medical and health sciences Genome editing Neoplasms Genotype Genetics medicine Humans CRISPR Induced pluripotent stem cell CRISPR/Cas9 lcsh:QH301-705.5 spliceosomal mutations Cell Proliferation lcsh:R5-920 Mutation Serine-Arginine Splicing Factors gene editing Cas9 Cell Biology Hematopoietic Stem Cells Phenotype myelodysplastic syndrome 3. Good health mutational cooperation Alternative Splicing SRSF2 030104 developmental biology lcsh:Biology (General) chr7q deletion Myelodysplastic Syndromes splicing factor mutations lcsh:Medicine (General) Developmental Biology |
| Zdroj: | Stem Cell Reports, Vol 10, Iss 5, Pp 1610-1624 (2018) Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | 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. Graphical Abstract Highlights • A panel of isogenic iPSCs with SRSF2 P95L mutation and del(7q) was generated • The contributions of each genetic lesion to phenotype were separated • Each genetic lesion could be linked to specific therapeutic vulnerabilities • Expandable hematopoietic progenitor cell lines facilitate drug testing 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. |
| Databáze: | OpenAIRE |
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