Reprogramming Factor Expression Leads to Tumor Development

The forced expression of Oct3/4, Sox2, Klf4, and Myc reprograms differentiated somatic cells to induced pluripotent stem cells (iPSC). During reprogramming, cells acquire properties such as self-renewal, unlimited proliferation, increased glycolysis, and global transcriptional changes that are similar to the properties of cancer cells. To determine whether reprogramming and cancer share common pathways, Ohnishi and colleagues generated an in vivo mouse reprogramming system in which chimeric mice were generated from embryonic stem cells (ESC) harboring a doxycycline-inducible polycistronic cassette encoding Oct3/4, Sox2, Klf4, and Myc. Extended doxycycline treatment quickly led to morbidity and resulted in mice with highly proliferative dysplastic lesions and teratomas in multiple organs, and reprogramming factor expression for 7 days followed by withdrawal of doxycycline led to the development of tumors consisting of undifferentiated dysplastic cells. Although doxycycline-withdrawn tumors arising in the kidney lost kidney cell identity gene expression and showed increased expression of ESC core pluripotency factors, some tumor cell–specific markers were expressed, and ESC Polycomb repressive complex targets were incompletely suppressed, suggesting that reprogramming in these tumors was incomplete. Epigenetic profiling revealed an increase in ESC-specific DNA methylation in tumor cells but with variable aberrations at imprinted genes. Of note, alterations in imprinted gene methylation and gene expression in doxycycline-withdrawn tumors resembled those observed in Wilms tumor, the most common pediatric kidney cancer, even though Wilms tumor-associated genes were not mutated, suggesting that reprogramming processes may play a role in the pathogenesis of this disease. Strikingly, iPSCs could be derived from doxycycline-withdrawn kidney tumor cells and contributed to the formation of tumor-free mice, indicating that the cancer phenotype was caused by reversible epigenetic alterations. In addition to showing that premature termination of reprogramming can lead to tumor development, these findings raise the possibility that some cancers may be exclusively driven by reprogramming-associated epigenetic alterations.

Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K, et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic deregulation. Cell 2014;156:663–77.

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