DEREGULATED EXPRESSION OF TCL1 CAUSES T-CELL LEUKEMIA IN MICE

The TCL1 oncogene on human chromosome 14q32.1 is involved in the devel opment of T cell leukemia in humans, These leukemias are classified ei ther as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age, The TCL1 oncogene is activ ated in these leukemias by juxtaposition to the alpha or beta locus of the T cell receptor, caused by chromosomal translocations t(14:14)(q1 1:q32), t(7:14)(q35:q32), or by inversions inv(14)(q11:q32). To show t hat transcriptional alteration of TCL1 is causally involved in the gen eration of T cell neoplasia we have generated transgenic mice that car ry the TCL1 gene under the transcriptional control of the p56(lck) pro moter element, The lck-TCL1 transgenic mice developed mature T cell le ukemias after a long latency period, Younger mice presented preleukemi c T cell expansions expressing TCL1, and leukemias developed only at a n older age, The phenotype of the murine leukemias is CD4(-)CD8(+), in contrast to human leukemias, which are predominantly CD4(+)CD8(-), Th ese studies demonstrate that transcriptional activation of the TCL1 pr otooncogene can cause malignant transformation of T lymphocytes, indic ating the role of TCL1 in the initiation of malignant transformation i n T prolymphocytic leukemias and T chronic lymphocytic leukemias.