Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: Parallels with E2A-deficient mice

The gene most commonly activated by chromosomal rearrangements in patients with T-cell acute lymphoblastic leukemia (T-ALL) is SCL/tal. In collaborati on 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 abnorm alities in terms of proliferation, apoptosis, clonality, and immunophenotyp e prior to the onset of a frank malignancy. At 4 weeks of age, thymocytes f rom SCL LMO1 mice show 70% fewer total thymocytes, with increased rates of both proliferation and apoptosis, than control thymocytes. At this age, a c lonal population of thymocytes begins to populate the thymus, as evidenced by oligoclonal T-cell-receptor gene rearrangements. Also, there is a dramat ic increase in immature CD44(+) CD25(-) cells, a decrease in the more matur e CD4(+) CD8(+) cells, and development of an abnormal CD44(+) CD8(+) popula tion. An identical pattern of premalignant changes is seen with either a fu ll-length SCL protein or an amino-terminal truncated protein which lacks th e 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 d evelop in E2A null mice, supporting the hypothesis that SCL exerts its onco genic action through a functional inactivation of E proteins.