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

Objective. TEL/PDGF beta R 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/PDGF beta R transforms cells. Materials and Methods. Activation of JAK: and STAT proteins was studied in an interleukin 3 (IL3)-dependent cell line, Ba/F3, transformed to IL-3 independence by TEL/PDGF beta R. Results. TEL/PDGF beta R activates STAT1 and STAT5 in transformed Ba/F3 cells through a JAK-independent pathway. Activation of STAT proteins requires the kinase activity of TEL/PDGF beta R, JAK1, JAK2, JAK3, and TYK2 are not phosphorylated by TEL/PDGR beta R. However, TEL/PDGF beta R can phosphorylate STAT5 in transiently transfected COS tells, suggesting that TEL/PDGF beta R may itself be the kinase involved in tyrosine phosphorylation of STAT proteins. In contrast, native PDGF beta R 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. Published by Elsevier Science Inc.