TEL/PDGF beta R induces hematologic malignancies in mice that respond to aspecific tyrosine kinase inhibitor

The TEL/PDGF beta R fusion protein is expressed as the consequence of a rec urring t(5;12) translocation associated with chronic myelomonocytic leukemi a (CMML). Unlike other activated protein tyrosine kinases associated with h ematopoietic malignancies, TEL/PDGF beta R is invariably associated with a myeloid leukemia phenotype in humans. To test the transforming properties o f TEL/PDGF beta R in vivo, and to analyze the basis for myeloid lineage spe cificity in humans, we constructed transgenic mice with TEL/PDGF beta R exp ression driven by a lymphoid-specific immunoglobulin enhancer-promoter cass ette. These mice developed lymphoblastic lymphomas of both T and B lineage, demonstrating that TEL/PDGF beta R is a transforming protein in vivo, and that the transforming ability of this fusion is not inherently restricted t o the myeloid lineage. Treatment of TEL/PDGF beta R transgenic animals with a protein tyrosine kinase inhibitor with in vitro activity against PDGF be ta R (CGP57148) resulted in suppression of disease and a prolongation of su rvival. A therapeutic benefit was apparent both in animals treated before t he development of overt clonal disease and in animals transplanted with clo nal tumor cells. These results suggest that small-molecule tyrosine kinase inhibitors may be effective treatment for activated tyrosine kinase-mediate d malignancies both early in the course of disease and after the developmen t of additional transforming mutations. (C) 1999 by The American Society of Hematology.