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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3891-3899
TEL-JAK2 transgenic mice develop T-cell leukemia
Clémence Carron,
Françoise Cormier,
Anne Janin,
Virginie Lacronique,
Marco Giovannini,
Marie-Thérèse Daniel,
Olivier Bernard, and
Jacques Ghysdael
From the Centre National de la Recherche Scientifique (CNRS) UMR
146-Institut Curie, Centre Universitaire, Orsay, France; Service
Central d'Anatomie et de Cytologie Pathologiques and INSERM U462
Laboratoire Central d'Hématologie, Hopital St. Louis, Paris,
France; and INSERM U434-CEPH, Paris, France.
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 EµSR 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 TCR 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.
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