[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: stem-cell myeloproliferative disorder (B-or T-cell lymphoblastic leukemia/lymphoma with myeloid hyperplasia and peripheral blood eosinophilia) and acute myeloid leukemia (myelomonocytic or monocytic with erythrophagocytosis). The FGFR1 and MOZ genes are rearranged in these diseases and encode one of the four fibroblast growth factor receptors and a 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 - lead to tumorigenesis through distinct pathways. The constitutive kinase activity triggered by dimerization mediated by the protein-protein interaction motifs of the FGFR1 protein partner regardless of external stimuli and the delocalization of the fusion proteins compared to their normal counterparts may lead to tumorigenesis presumably by inducing inappropriate recruitment in the cytoplasm of signaling substrates. Currently, little is known about the precise role of MOZ in the regulation of gene transcription. However, all the aberrant proteins described to date retain the MOZ histone acetyltransferase domain 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 number of translocations affecting FGFR1 and MOZ strongly suggest their involvement in oncogenic processes and point to these proteins as potential therapeutical targets.
Pébusque
M J
MJ
Laboratoire d'oncologie moléculaire, Inserm U. 119, IFR57, 27, boulevard Leï-Roure, 13009 Marseille, France.
Chaffanet
M
M
Popovici
C
C
Birnbaum
D
D
D000123:Acetyltransferases / Q000235:genetics* / Q000502:physiology; D000208:Acute Disease; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015321:Gene Rearrangement / Q000235:genetics; D006410:Hematopoiesis / Q000502:physiology; D051548:Histone Acetyltransferases; D006801:Humans; D007930:Leucine / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000502:physiology; D014178:Translocation, Genetic / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics
C117597:CEP43 protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D007930:Leucine