FGFR1 and MOZ, two key genes involved in malignant hemopathies linked to rearrangements within the chromosomal region 8p11-12

Two distinct clinical syndromes have been associated with the p11.12 region of the short arm of chromosome 8: stern-cell myeloproliferative disorder ( B-or T-cell lymphoblastic leukemial/lymphoma with myeloid hyperplasia and p eripheral blood eosinophilia) and acute myeloid leukemia (myelomonocytic or monocytic with erythrophagocy- The FGFR1 and MOZ genes are rearranged) in these diseases and encode one of the four fibroblast growth factor receptor s and member of a novel histone acetyltransferase family respectively. The predicted fusion proteins that are putatively oncogenic - FOP-FGFR1, CEP110 -FGFR1, and FIM-FGFR1 - and - MOZ-CBP, MOZ-p300, and MOZ-TIF2 - lend to tum origensis through distinct pathways. The constitutive kinase activity trigg ered by dimerization mediated by the protein-protein interaction motifs of the FGFR1 protein partner regardless of external stimuli and the delocaliza tion of the fusion proteins compared to their normal counterparts may lead so tumorigenesis Presumably by inducing inappropriate recruitment in the cy toplasm of signaling substrates. Currently little is Known about the precis e role of MOZ in the regulation of gene transcription. However, all the abe rrant proteins described to date retain the MOZ histone acetyltransferase d omain fused to that of the transcription coactivators CBP, p300, and TIF2. The fusion of two acetyltransferases whose activity may be mistargetted or misregulated could be a critical event in leukemogenesis. The increasing nu mber of translocations affecting FGFR1 and MOZ strongly suggest their invol vement in oncogenic processes and point to these proteins as potential ther apeutical targets.