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RESEARCH PAPER
1 Whitehead Institute for Biomedical Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA; 2 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA; 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02115, USA
We have used nuclear transplantation to test whether the reprogramming activity of oocytes can reestablish developmental pluripotency of malignant cancer cells. We show here that the nuclei of leukemia, lymphoma, and breast cancer cells could support normal preimplantation development to the blastocyst stage but failed to produce embryonic stem (ES) cells. However, a blastocyst cloned from a RAS-inducible melanoma nucleus gave rise to ES cells with the potential to differentiate into multiple cell types in vivo including melanocytes, lymphocytes, and fibroblasts. Chimeras produced from these ES cells developed cancer with higher penetrance, shorter latency, and an expanded tumor spectrum when compared with the donor mouse model. These results demonstrate that the secondary changes of a melanoma nucleus are compatible with a broad developmental potential but predispose mice to melanomas and other malignant tumors on reactivation of RAS. Our findings serve as a paradigm for studying the tumorigenic effect of a given cancer genome in the context of a whole animal.
[Keywords: Cancer; epigenetics; nuclear transfer; reprogramming; pluripotency; embryonic stem cells]
Received April 21, 2004; revised version accepted June 2, 2004.
4 These authors contributed equally to this work.
5 E-MAIL Lynda_Chin{at}dfci.harvard.edu; FAX (617) 632-6069.
6 E-MAIL jaenisch{at}wi.mit.edu; FAX (617) 258-6505.
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