The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins

This report describes 2 patients with a clinical and hematologic diagnosis of chronic myeloid leukemia (CML) in chronic phase who had an acquired t(8; 22)(p11;q11). Analysis by fluorescence in situ hybridization (FISH) and rev erse transcription-polymerase chain reaction (RT-PCR) indicated that both p atients were negative for the BCR-ABL fusion, but suggested that the BCR ge ne was disrupted. Further FISH indicated a breakpoint within fibroblast gro wth factor receptor 1 (FGFR1), the receptor tyrosine kinase that is known t o be disrupted in a distinctive myeloproliferative disorder, most commonly by fusion to ZNF198. RT-PCR confirmed the presence in both cases of an in-f rame messenger RNA fusion between SCR exon 4 and FGFR1 exon 9. Expression o f BCR-FGFR1 in the factor-dependent cell line Ba/F3 resulted in interleukin 3-independent clones that grew at a comparable rate to cells transformed w ith ZNF198-FGFR1. The growth of transformed cells was inhibited by the phos phatidylinositol 3-kinase inhibitor LY294002, the farnesyltransferase inhib itors L744832 and manumycin A, the p38 inhibitors SB202190 and SB203580 but not by the MEK inhibitor PD98059. The growth of BaF3/BCR-FGFR1 and BaF3/ZN F198-FGFR1 was not significantly inhibited by treatment with STI571, but wa s Inhibited by SU5402, a compound with inhibitory activity against FGFR1. I nhibition with this compound was associated with decreased phosphorylation of ERK1/2 and BCR-FGFR1 or ZNF198-FGFR1, and was dose dependent with an Inh ibitory concentration of 50% of approximately 5 muM. As expected, growth of BaF3/BCR-ABL was Inhibited by STI571 but not by SU5402. The study demonstr ates that the BCR-FGFR1 fusion may occur In patients with apparently typica l CIVIL. Patients with constitutively active FGFR1 fusion genes may be amen able to treatment with specific FGFR1 Inhibitors. (C) 2001 by The American Society of Hematology.