TEL-JAK2 transgenic mice develop T-cell leukemia

We previously reported a fusion between TEL and JAK2 in a t(9;12)(p24;p13) chromosomal translocation in childhood acute T-cell leukemia, This fusion g ene encodes a TEL-JAK2 chimeric protein in which the 336 amino-terminal res idues of TEL, including its specific self-association domain, are fused to the kinase domain of JAK2, TEL-JAK2 exhibits constitutive activation of its tyrosine kinase activity which, in turn, confers growth factor-independent proliferation to the interleukin-3-dependent Ba/F3 hematopoietic cell line . To elucidate the properties of TEL-JAK2 in primary cells and to create an animal model for TEL-JAK2-induced leukemia, we generated transgenic mice i n which the TEL-JAK2 complementary DNA was placed under the transcriptional control of the E mu SR alpha enhancer/promoter. TEL-JAK2 founder mice and their transgenic progeny developed fatal leukemia at 4 to 22 weeks of age. Selective amplification of CD8-positive T cells was observed in blood, lymp h nodes, thymus, spleen, and bone marrow. Expression of a tyrosine-phosphor ylated TEL-JAK2 protein and activation of STAT1 and STATE (signal transduce r and activator of transcription) were detected in leukemic tissues. TEL-JA K2 diseased mice also displayed invasion of nonhematopoietic organs, includ ing liver, brain, lung, and kidney, by leukemic T cells. Leukemic organs of founder and transgenic progeny contained a monoclonal/oligoclonal T-cell p opulation as analyzed by the rearrangement of the TCR beta locus. Transplan tation of TEL-JAK2 leukemic cells in nude mice confirmed their invasive nat ure. We conclude that the TEL-JAK2 fusion is an oncogene in vivo and that i ts expression in lymphoid cells results in the preferential expansion of CD 8-positive T cells. (C) 2000 by The American Society of nematology.