TEL/PDGFβR fusion protein activates STAT1 and STAT5: A common mechanism for transformation by tyrosine kinase fusion proteins

Objective. TEL/PDGFβR is a tyrosine kinase fusion protein associated with the pathogenesis of chronic myelomonocytic leukemia. The following experiments were undertaken to understand the mechanisms whereby TEL/PDGFβR transforms cells. Materials and Methods. Activation of JAK and STAT proteins was studied in an interleukin 3 (IL-3)-dependent cell line, Ba/F3, transformed to IL-3 independence by TEL/PDGFβR. Results. TEL/PDGFβR activates STAT1 and STAT5 in transformed Ba/F3 cells through a JAK- independent pathway. Activation of STAT proteins requires the kinase activity of TEL/PDGFβR. JAK1, JAK2, JAK3, and TYK2 are not phosphorylated by TEL/PDGFβR. However, TEL/PDGFβR can phosphorylate STAT5 in transiently transfected COS cells, suggesting that TEL/PDGFβR may itself be the kinase involved in tyrosine phosphorylation of STAT proteins. In contrast, native PDGFβR stimulated by PDGF ligand does not activate STAT proteins to a significant degree in this hematopoietic context. STAT1 and STAT5 also are activated by TEL/ABL and TEL/JAK2 fusion proteins associated with human leukemia. Conclusions. STAT activation may be a common mechanism of transformation by leukemogenic tyrosine kinase fusion proteins. (C) 2000 International Society for Experimental Hematology.