Chromosomal translocations involving the
platelet-derived growth factor beta receptor (PDGFbetaR) gene have been reported in some patients with
chronic myelomonocytic leukemia (CMML). The resultant fusion
proteins have constitutive PDGFbetaR
tyrosine kinase activity, but the partner genes previously reported (tel, Huntingtin interacting
protein 1 [HIP-1], H4/D10S170) have poorly understood roles in the oncogenic activity of the fusion
proteins. A novel PDGFbetaR fusion
protein has been characterized in a patient with CMML and an acquired t(5;17)(q33;p13). Southern blot analysis on patient
leukemia cells demonstrated involvement of the PDGFbetaR gene. Using 5' rapid amplification of
complementary DNA ends-polymerase chain reaction (RACE-PCR) on patient
RNA, rabaptin-5 was identified as a novel partner fused in-frame to the PDGFbetaR gene. The new fusion
protein includes more than 85% of the native Rabaptin-5 fused to the transmembrane and intracellular
tyrosine kinase domains of the PDGFbetaR. Transduction with a retroviral vector expressing rabaptin-5/PDGFbetaR transformed the hematopoietic cell line Ba/F3 to
growth factor independence and caused a fatal myeloproliferative disease in mice. Rabaptin-5 is a well-studied
protein shown to be an essential and rate-limiting component of early endosomal fusion through interaction with the Ras family
GTPases Rab5 and Rab4. The fusion
protein includes 3 of 4 coiled-coil domains (involved in homodimerization of native rabaptin-5), 2
caspase-3 cleavage sites, and a binding site for the tumor suppressor gene
tuberin (
tuberous sclerosis complex-2). Early endosomal transport is critical in regulation of various
growth factor receptors, through
ligand-induced
clathrin-mediated endocytosis, and thus this new fusion
protein links together 2 important pathways of growth regulation.