Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia

Chromosomal translocations involving the platelet-derived growth factor bet a receptor (PDGF betaR) gene have been reported in some patients with chron ic myelomonocytic leukemia (CMML). The resultant fusion proteins have const itutive PDGF betaR tyrosine kinase activity, but the partner genes previous ly reported (tel, Huntingtin interacting protein 1 [HIP-1], H4/D10S170) hav e poorly understood roles in the oncogenic activity of the fusion proteins. A novel PDGF betaR fusion protein has been characterized in a patient with CMML and an acquired t(5;17)(q33;p13). Southern blot analysis on patient l eukemia cells demonstrated involvement of the PDGF betaR gene. Using 5' rap id 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 PDGF betaR gene. The new fusion protein includes more than 85% of the native Rabaptin-5 fused to the transmembrane and intracellular tyro sine kinase domains of the PDGF betaR. Transduction with a retroviral vecto r expressing rabaptin-5/PDGF betaR transformed the hematopoietic cell line Ba/F3 to growth factor independence and caused a fatal myeloproliferative d isease in mice. Rabaptin-5 is a well-studied protein shown to be an essenti al and rate-limiting component of early endosomal fusion through interactio n 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 c ritical in regulation of various growth factor receptors, through ligand-in duced clathrin-mediated endocytosis, and thus this new fusion protein links together 2 important pathways of growth regulation. (Blood. 2001;98:2518-2 525) 2001 by The American Society of Hematology.