Fusion of the BCR and the fibroblast growth factor receptor-1 (FGFR1) genes as a result of t(8;22)(p11;q11) in a myeloproliferative disorder: The first fusion gene involving BCR but not ABL

Constitutive activation of tyrosine kinases as a consequence of chromosomal translocations, forming fusion genes, plays an important role in the devel opment of hematologic malignancies, in particular, myeloproliferative syndr omes (MPSs). In this respect, the t(9;22)(q34;q11) that results in the BCR/ ABL fusion gene in chronic myeloid leukemia is one of the best-studied exam ples. The fibroblast growth factor receptor 1 (FGFR1) gene at 8p11 encodes a transmembrane receptor tyrosine kinase and is similarly activated by chro mosomal translocations, in which three alternative genes-ZNF198 at 13q12, C EP110 at 9q34, and FOP at 6q27-become fused to the tyrosine kinase domain o f FGFR1. These 8p11-translocations are associated with characteristic morph ologic and clinical features, referred to as "8p11 MPS." In this study, we report the isolation and characterization of a novel fusion gene in a hemat ologic malignancy with a t(8;22)(p11;q11) and features suggestive of 8p11 M PS. We show that the breakpoints in the t(8;22) occur within introns 4 and 8 of the BCR and FGFR1 genes, respectively. On the mRNA level, the t(8;22) results in the fusion of BCR exons 1-4 in-frame with the tyrosine kinase do main of FGFR1 as well as in the expression of a reciprocal FGFR1/BCR chimer ic transcript. By analogy with data obtained from previously characterized fusion genes involving FGFR1 and BCR/ABL, it is likely that the oligomeriza tion domain contributed by BCR is critical and that its dimerizing properti es lead to aberrant FGFR1 signaling and neoplastic transformation. (C) 2001 Wiley-Liss, Inc.