title: The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q.
abstract: We have isolated the human GRAF gene (for GTPase regulator associated with the focal adhesion kinase pp125(FAK)). This gene was fused with MLL in a unique t(5;11)(q31;q23) that occurred in an infant with juvenile myelomonocytic leukemia. GRAF encodes a member of the Rho family of the GTPase-activating protein (GAP) family. On the protein level, it is 90% homologous to the recently described chicken GRAF gene that functions as a GAP of RhoA in vivo and is thus a critical component of the integrin signaling transduction pathway. The particular position of the human GRAF gene at 5q31 and the proposed antiproliferative and tumor suppressor properties of its avian homologue suggest that it also might be pathogenetically relevant for hematologic malignancies with deletions of 5q. To investigate this possibility, we sequenced 4-5 individual cDNA clones from 13 cases in which one allele of GRAF was deleted. We found point mutations within the GAP domain of the second GRAF allele in one patient. In two additional patients we found an insertion of 52 or 74 bp within the GRAF cDNA that generates a reading frame shift followed by a premature stop codon. GRAF maps outside the previously defined commonly deleted 5q31 region. Nevertheless, inactivation of both alleles in at least some cases suggests that deletions and mutations of the GRAF gene may be instrumental in the development and progression of hematopoeitic disorders with a del(5q).
authors.affiliation: Departments of General Pediatrics, Hematology, and Oncology, and Pathology, University of Giessen, D-35392-Giessen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Borkhardt
authors.forename: S
authors.initials: S
authors.lastname: Bojesen
authors.forename: O A
authors.initials: OA
authors.lastname: Haas
authors.forename: U
authors.initials: U
authors.lastname: Fuchs
authors.forename: D
authors.initials: D
authors.lastname: Bartelheimer
authors.forename: I F
authors.initials: IF
authors.lastname: Loncarevic
authors.forename: R M
authors.initials: RM
authors.lastname: Bohle
authors.forename: J
authors.initials: J
authors.lastname: Harbott
authors.forename: R
authors.initials: R
authors.lastname: Repp
authors.forename: U
authors.initials: U
authors.lastname: Jaeger
authors.forename: S
authors.initials: S
authors.lastname: Viehmann
authors.forename: T
authors.initials: T
authors.lastname: Henn
authors.forename: P
authors.initials: P
authors.lastname: Korth
authors.forename: D
authors.initials: D
authors.lastname: Scharr
authors.forename: F
authors.initials: F
authors.lastname: Lampert
mesh_terms: D019677:Artificial Gene Fusion; D001483:Base Sequence; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002895:Chromosomes, Human, Pair 5; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes; D014157:Transcription Factors; D014178:Translocation, Genetic
chemical_list: C115971:ARHGAP26 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase