CONSISTENT FUSION OF ZNF198 TO THE FIBROBLAST-GROWTH-FACTOR RECEPTOR-1 IN THE T(8-13)(P11-Q12) MYELOPROLIFERATIVE SYNDROME

The 8p11 myeloproliferative syndrome is a rare, aggressive condition a ssociated with reciprocal translocations of chromosome band 8p11, most commonly the t(8;13)(p11;q12). To identify the genes involved in this translocation, we used fluorescence in situ hybridization (FISH) anal ysis to show that the chromosome 8 breakpoints fel within YAC 899e2 an d that the chromosome 13 breakpoints are clustered in a region flanked by YACs 929f11 and 911h8. FISH using chromosome 13 PAC clones indicat ed that the t(8;13) is not simply a reciprocal translocation but also involves an inversion of 13q11-12. Exon trapping of a PAC that spanned the chromosome 13 translocation breakpoints led to the identification of a gene, ZNF198, that detected rearranged bands when used as a prob e against Southern blots of patient DNA. Conceptual translation of the full-length ZNF198 cDNA sequence predicts a protein of 1377 amino aci ds that shows significant homology to the DXS6673E/KIAA0385 and KIAA04 25 proteins. Alignment of these three proteins revealed a novel, conse rved Zn-finger-related motif (MYM domain) of the general form CX2C19-2 2CX3CX13-19CX2CX19-25FCX3CX3F/Y that is repeated five times in each pr otein. To identify the translocation partner gene on chromosome 8, 5' and 3' RACE polymerase chain reactions (PCRs) were performed on patien t RNA with several combinations of ZNF198 primers. Clones were identif ied in which the ZNF198 was fused to exon 9 of the fibroblast growth f actor receptor-1 (FGFR1), a gene known to map to 8p11. An identical ZN F198-FGFR1 fusion was detected in the three patients with a t(8;13) fo r whom RNA was available; reciprocal FGFR1-ZNF198 transcripts were not detected. Rearrangements of both ZNF198 and FGFR1 were found in two f urther patients by Southern blotting. ZNF198-FGFR1 includes the five M YM domains of ZNF198 and the intracellular tyrosine kinase domain of F GFR1. We hypothesize that this fusion leads to constitutive activation of the FGFR1 tyrosine kinase in a manner analogous to the activation of ABL by BCR in chronic myeloid leukemia. (C) 1998 by The American So ciety of Hematology.