Pear, Warren S. and Aster, Jon C. and Scott, Martin L. and Hasserjian, Robert P. and Soffer, Benny and Sklar, Jeffrey and Baltimore, David (1996) Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. Journal of Experimental Medicine, 183 (5). pp. 2283-2291. ISSN 0022-1007 http://resolver.caltech.edu/CaltechAUTHORS:PEAjem96
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Notch is a highly conserved transmembrane protein that is involved in cell fate decisions and is found in organisms ranging from Drosophila to humans. A human homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint of a subset of T-cell lymphoblastic leukemias/lymphomas containing a t(7;9) chromosomal translocation; however, its role in oncogenesis has been unclear. Using a bone marrow reconstitution assay with cells containing retrovirally transduced TAN1 alleles, we analyzed the oncogenic potential of both nuclear and extranuclear forms of truncated TAN1 in hematopoietic cells. Although the Moloney leukemia virus long terminal repeat drives expression in most hematopoietic cell types, retroviruses encoding either form of the TAN1 protein induced clonal leukemias of exclusively immature T cell phenotypes in approximately 50% of transplanted animals. All tumors overexpressed truncated TAN1 of the size and subcellular localization predicted from the structure of the gene. These results show that TAN1 is an oncoprotein and suggest that truncation and overexpression are important determinants of transforming activity. Moreover, the murine tumors caused by TAN1 in the bone marrow transplant model are very similar to the TAN1-associated human tumors and suggest that TAN1 may be specifically oncotropic for T cells.
|Additional Information:||Copyright © 1996 by Rockefeller University Press. RUP grants the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode. Received for publication 5 January 1996. We thank Dr. C. Guidos and members of the Baltimore and Sklar laboratories for helpful discussions. We also thank Dr. G. Pinkus for help with immunohistochemistry, and V. Patriuvavicius for technical assistance. We gratefully acknowledge Dr. K. LaMarco and Dr. W. Sha for critical reading of the manuscript. W.S. Pear was supported by a Physician Postdoctoral Fellowship from the Howard Hughes Medical Institute and is presently a Special Fellow of the Leukemia Society of America. J.C. Aster is supported by a Research Grant from the Massachusetts Division of the American Cancer Society. R.P. Hasserjian is supported by National Institutes of Health training grant number 5T32HL-07627. This work was supported by National Institutes of Health grant number CA-38621 to J. Sklar and 7R37AI-2234613 to D. Baltimore.|
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