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 gene encodes a TEL-JAK2 chimeric protein in which the 336 amino-terminal residues 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 in which the TEL-JAK2 complementary DNA was placed under the transcriptional control of the EmuSRalpha 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, lymph nodes, thymus, spleen, and bone marrow. Expression of a tyrosine-phosphorylated TEL-JAK2 protein and activation of STAT1 and STAT5 (signal transducer and activator of transcription) were detected in leukemic tissues. TEL-JAK2 diseased mice also displayed invasion of nonhematopoietic organs, including liver, brain, lung, and kidney, by leukemic T cells. Leukemic organs of founder and transgenic progeny contained a monoclonal/oligoclonal T-cell population as analyzed by the rearrangement of the TCRbeta locus. Transplantation of TEL-JAK2 leukemic cells in nude mice confirmed their invasive nature. We conclude that the TEL-JAK2 fusion is an oncogene in vivo and that its expression in lymphoid cells results in the preferential expansion of CD8-positive T cells. (Blood. 2000;95:3891-3899)
Carron
C
C
Centre National de la Recherche Scientifique (CNRS) UMR 146-Institut Curie, Centre Universitaire, Orsay, France.
Cormier
F
F
Janin
A
A
Lacronique
V
V
Giovannini
M
M
Daniel
M T
MT
Bernard
O
O
Ghysdael
J
J
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018076:DNA, Complementary; D004742:Enhancer Elements, Genetic; D006801:Humans; D015458:Leukemia, T-Cell / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007958:Leukocyte Count; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014158:Transcription, Genetic; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
D018076:DNA, Complementary; D015514:Oncogene Proteins, Fusion; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein; C491568:TEL-JAK2 fusion protein, mouse