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 development of hematologic malignancies, in particular, myeloproliferative syndromes (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 examples. The fibroblast growth factor receptor 1 (FGFR1) gene at 8p11 encodes a transmembrane receptor tyrosine kinase and is similarly activated by chromosomal translocations, in which three alternative genes-ZNF198 at 13q12, CEP110 at 9q34, and FOP at 6q27-become fused to the tyrosine kinase domain of FGFR1. These 8p11-translocations are associated with characteristic morphologic and clinical features, referred to as "8p11 MPS." In this study, we report the isolation and characterization of a novel fusion gene in a hematologic malignancy with a t(8;22)(p11;q11) and features suggestive of 8p11 MPS. 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 domain of FGFR1 as well as in the expression of a reciprocal FGFR1/BCR chimeric transcript. By analogy with data obtained from previously characterized fusion genes involving FGFR1 and BCR/ABL, it is likely that the oligomerization domain contributed by BCR is critical and that its dimerizing properties lead to aberrant FGFR1 signaling and neoplastic transformation.
Fioretos
T
T
Department of Clinical Genetics, Lund University Hospital, Sweden. Thoas.Fioretos@klingen.lu.se
Panagopoulos
I
I
Lassen
C
C
Swedin
A
A
Billström
R
R
Isaksson
M
M
Strömbeck
B
B
Olofsson
T
T
Mitelman
F
F
Johansson
B
B
D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D019457:Chromosome Breakage / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009196:Myeloproliferative Disorders / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D014158:Transcription, Genetic; D014178:Translocation, Genetic / Q000235:genetics*
D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; C496348:FGFR1 protein, human; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr