Generation of iPSCs from cultured human malignant cells

Blood. 2010 May 20;115(20):4039-42. doi: 10.1182/blood-2009-07-231845. Epub 2010 Mar 16.

Abstract

Induced pluripotent stem cells (iPSCs) can be generated from various differentiated cell types by the expression of a set of defined transcription factors. So far, iPSCs have been generated from primary cells, but it is unclear whether human cancer cell lines can be reprogrammed. Here we describe the generation and characterization of iPSCs derived from human chronic myeloid leukemia cells. We show that, despite the presence of oncogenic mutations, these cells acquired pluripotency by the expression of 4 transcription factors and underwent differentiation into cell types derived of all 3 germ layers during teratoma formation. Interestingly, although the parental cell line was strictly dependent on continuous signaling of the BCR-ABL oncogene, also termed oncogene addiction, reprogrammed cells lost this dependency and became resistant to the BCR-ABL inhibitor imatinib. This finding indicates that the therapeutic agent imatinib targets cells in a specific epigenetic differentiated cell state, and this may contribute to its inability to fully eradicate disease in chronic myeloid leukemia patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Imatinib Mesylate
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Pyrimidines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction

Substances

  • Benzamides
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • MYC protein, human
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Pyrimidines
  • RNA, Messenger
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl