Juxtamembrane Domain Truncation Is Sufficient for Activation of the FIP1L1-PDGFRα and ETV6-PDGFRβ Fusion Kinases.

Tyrosine kinase fusions such as BCR-ABL are common causes of myeloproliferative diseases and hematopoietic malignancies. Frequently, enforced dimerization by the fusion partner protein confers ligand-independent activation on these fusion kinases. FIP1L1-PDGFRα is a fusion kinase implicated in chronic eosinophilic leukemia and systemic mast cell disease. Recently, we showed that the partner protein FIP1L1 is not, in fact, required for PDGFRα activation in vitro or in vivo. We now demonstrate that truncation of the PDGFRα juxtamembrane (JM) domain is sufficient for kinase activation and subsequent transformation of Ba/F3 cells to growth factor independence, even in the absence of FIP1L1. In contrast, the presence of a complete JM domain is inhibitory to PDGFRα kinase activation. These findings are consistent with clinical data from patients with the FIP1L1-PDGFRα fusion, in which the breakpoints in PDGFRA are always tightly clustered within the JM domain. Furthermore, our results suggest that disruption of the JM domain, which has an autoinhibitory function in some type III receptor tyrosine kinases (RTKs), may contribute to activation of chimeric kinases. Notably, we observed a similar effect of JM domain truncation in a related type III RTK, PDGFRβ. Fusion of PDGFRB to various partner proteins, such as ETV6, can cause chronic myelomonocytic leukemia. However, we show that PDGFRβ kinase activation and signaling to downstream targets can be achieved in the absence of ETV6 via truncation of PDGFRB within the JM domain. These results suggest that disruption of an autoinhibitory JM domain may be an alternative, dimerization-independent mechanism of aberrant regulation of activated kinases involved in hematopoietic and other malignancies.