TEL-JAK2 transgenic mice develop T-cell leukemia

Abstract

We previously reported a fusion between TEL and JAK2in 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 TCRβ 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.

Molecular‐genetic insights in paediatric T‐cell acute lymphoblastic leukaemia

“…The ETV6-JAK2 fusion gene was identified in a t(9;12)(p24;p13) positive T-ALL patient, resulting in constitutive tyrosine kinase activity (Lacronique et al, 1997). The leukaemogenic role of this fusion protein was subsequently shown in an ETV6-JAK2 mouse model, which developed T-cell leukaemias with high penetrance (Carron et al, 2000).…”

A BCR–JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia

“…Whereas ETV6-JAK2 fusion genes were observed in a B-and a T-lineage acute lymphoblastic leukemia (ALL) case (Lacronique et al, 1997;Peeters et al, 1997), this fusion also was observed in association with an ETV6-MDS-1/EVI-1 rearrangement in a CML (Peeters et al, 1997), leaving open the question of whether JAK2 fusion genes alone can be associated with myeloid leukemia. In addition, whereas retroviral gene transfer of ETV6-JAK2 induced both myelo-and lymphoproliferative disease in a murine bone marrow transplant model (Schwaller et al, 1998), ETV6-JAK2 transgenic mice developed only T-cell leukemia (Carron et al, 2000).…”

FoxN1-dependent thymic epithelial cells promote T-cell leukemia development

“…Diseased TJ2-Tg mice present large thymic lymphomas with loss of cortico-medullary demarcation and frequent disruption of the thymic capsule (32,35). By performing immunohistological analyses against thymic keratin proteins, we observed that TJ2-Tg mouse thymic lymphomas developed conspicuous KNAs, which were more extensive in larger lymphomas.…”

“…Thymic lymphomas from TJ2-Tg mice often become 10-20 times larger than age-matched control thymi and lose the typical thymic compartmentalization in cortex and medulla (35,37). To determine whether the thymic microenvironment influences TJ2-Tg-induced leukemogenesis, we began by assessing the spatial distribution of several thymic stromal cells in diseased mice.…”