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Molecular and Cellular Biology, July 1999, p. 5025-5035, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Disordered T-Cell Development and T-Cell Malignancies in SCL LMO1 Double-Transgenic Mice: Parallels with E2A-Deficient Mice

David S. Chervinsky,1,2 Xian-Feng Zhao,1,2 Du H. Lam,2,3 MaryKay Ellsworth,4 Kenneth W. Gross,4 and Peter D. Aplan1,2,5,*

Departments of Cancer Genetics,1 Pediatrics,2 Molecular Immunology,3 and Molecular and Cellular Biology,4 Roswell Park Cancer Institute, Buffalo, New York 14263, and Children's Hospital of Buffalo, Buffalo, New York 142225

Received 19 October 1998/Returned for modification 7 December 1998/Accepted 26 March 1999

The gene most commonly activated by chromosomal rearrangements in patients with T-cell acute lymphoblastic leukemia (T-ALL) is SCL/tal. In collaboration with LMO1 or LMO2, the thymic expression of SCL/tal leads to T-ALL at a young age with a high degree of penetrance in transgenic mice. We now show that SCL LMO1 double-transgenic mice display thymocyte developmental abnormalities in terms of proliferation, apoptosis, clonality, and immunophenotype prior to the onset of a frank malignancy. At 4 weeks of age, thymocytes from SCL LMO1 mice show 70% fewer total thymocytes, with increased rates of both proliferation and apoptosis, than control thymocytes. At this age, a clonal population of thymocytes begins to populate the thymus, as evidenced by oligoclonal T-cell-receptor gene rearrangements. Also, there is a dramatic increase in immature CD44+ CD25- cells, a decrease in the more mature CD4+ CD8+ cells, and development of an abnormal CD44+ CD8+ population. An identical pattern of premalignant changes is seen with either a full-length SCL protein or an amino-terminal truncated protein which lacks the SCL transactivation domain, demonstrating that the amino-terminal portion of SCL is not important for leukemogenesis. Lastly, we show that the T-ALL which develop in the SCL LMO1 mice are strikingly similar to those which develop in E2A null mice, supporting the hypothesis that SCL exerts its oncogenic action through a functional inactivation of E proteins.

* Corresponding author. Mailing address: Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY 14263. Phone: (716) 845-5773. Fax: (716) 845-4502. E-mail: paplan{at}sc3101.med.buffalo.edu.

Molecular and Cellular Biology, July 1999, p. 5025-5035, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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