Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells

The involvement of the cytokine signaling pathway in oncogenesis has long b een postulated. Recently, rearrangements of the gene encoding the tyrosine janus kinase 2 (JAK2) have been reported in human leukemias indicating a di rect JAK-signal transduction and activator of transcription (STAT)-mediated leukemic process. The leukemia-associated TEL-JAK2 fusion protein is forme d by the oligomerization domain of the translocated ets leukemia (TEL) prot ein fused to the Catalytic domain of JAK2, TEL-mediated oligomerization res ults in a constitutive tyrosine kinase activity that, in turn, is able to c onfer growth factor independence to the murine hematopoietic interleukin-3 (IL-3)-dependent Ba/F3 cell line. Results of the present study indicate tha t fusion proteins containing the oligomerization domain of TEL and the tyro sine kinase domains of Jak1, Jak2, JAK3, or TYK2 share similar properties a nd are able to efficiently substitute for the survival and mitogenic signal s controlled by IL-3, without concomitant activation of the IL-3 receptor, Electrophoretic mobility shift assays demonstrated Stat5 as the only activa ted Stat factor in TEL-Jak2- and TEL-Jak1-expressing cells, whereas other S tats, namely Stat1 and Stat3, could be detected in TEL-JAK3-, TEL-TYK2-, an d also in TEL-ABL-expressing Ba/F3 cells. High levels of expression of the Stat5-target genes pim-l, osm, and Cis were observed In all the cytokine-in dependent cell lines. Furthermore, the expression of a dominant negative fo rm of Stat5A markedly interfered with the growth factor independence proces s mediated by TEL-Jak2 in Ba/F3 cells. Because the BCR-ABL and TEL-PDGF bet a R oncoproteins also activate Stat5, activation of this factor should be a crucial step in activated tyrosine kinase-mediated leukemogenesis. (C) 200 0 by The American Society of Hematology.