Dissecting the Contributions of Cooperating Gene Mutations to Cancer Phenotypes and Drug Responses with Patient-Derived iPSCs

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

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1610-1624
Number of pages15
JournalStem Cell Reports
Volume10
Issue number5
DOIs
StatePublished - 8 May 2018

Keywords

  • CRISPR/Cas9
  • SRSF2
  • chr7q deletion
  • gene editing
  • induced pluripotent stem cells
  • mutational cooperation
  • myelodysplastic syndrome
  • spliceosomal mutations
  • splicing factor mutations

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