T-cell receptor-driven lymphomagenesis in mice derived from a reprogrammed T cell

The conversion of mature somatic cells into pluripotent stem cells, both by nuclear transfer and transduction with specific "reprogramming" genes, represents a major advance in regenerative medicine. Pluripotent stem cell lines can now be generated from an individual's own cells, faci...

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Bibliographic Details
Main Authors: Serwold, T. (Author), Hochedlinger, K. (Author), Swindle, J. (Author), Hedgpeth, J. (Author), Weissman, I. L. (Author), Jaenisch, Rudolf (Contributor)
Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor)
Format: Article
Language:English
Published: National Academy of Sciences (U.S.), 2018-06-18T20:44:36Z.
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042 |a dc 
100 1 0 |a Serwold, T.  |e author 
100 1 0 |a Massachusetts Institute of Technology. Department of Biology  |e contributor 
100 1 0 |a Jaenisch, Rudolf  |e contributor 
700 1 0 |a Hochedlinger, K.  |e author 
700 1 0 |a Swindle, J.  |e author 
700 1 0 |a Hedgpeth, J.  |e author 
700 1 0 |a Weissman, I. L.  |e author 
700 1 0 |a Jaenisch, Rudolf  |e author 
245 0 0 |a T-cell receptor-driven lymphomagenesis in mice derived from a reprogrammed T cell 
260 |b National Academy of Sciences (U.S.),   |c 2018-06-18T20:44:36Z. 
856 |z Get fulltext  |u http://hdl.handle.net/1721.1/116387 
520 |a The conversion of mature somatic cells into pluripotent stem cells, both by nuclear transfer and transduction with specific "reprogramming" genes, represents a major advance in regenerative medicine. Pluripotent stem cell lines can now be generated from an individual's own cells, facilitating the generation of immunologically acceptable stem cell-based therapeutics. Many cell types can undergo nuclear reprogramming, leading to the question of whether the identity of the reprogrammed cell of origin has a biological consequence. Peripheral blood, containing a mixture of T, B, NK, and myeloid cell types, represents one potential source of reprogrammable cells. In this study, we describe the unique case of mice derived from a reprogrammed T cell. These mice have prerearranged T-cell receptor (TCR) genes in all cells. Surprisingly, ≈50% of mice with prerearranged TCR genes develop spontaneous T cell lymphomas, which originate in the thymus. The lymphomas arise from developing T cells, and contain activated Notch1, similar to most human and mouse T-cell acute lymphoblastic lymphomas. Furthermore, lymphomagenesis requires the expression of both prerearranged TCRα and TCRβ genes, indicating a critical role for TCR signaling. Furthermore, inhibitors of multiple branches of TCR signaling suppress lymphoma growth, implicating TCR signaling as an essential component in lymphoma proliferation. The lymphomagenesis in mice derived from a reprogrammed T cell demonstrates the deleterious consequences of misregulation of the TCR rearrangement and signaling pathways and illustrates one case of cellular reprogramming where the identity of the cell of origin has profound consequences. Keywords: induced pluripotent stem cells; lymphoma; notch; receptor-mediated leukemogenesis; T cell receptor 
655 7 |a Article 
773 |t Proceedings of the National Academy of Sciences