Open AccessThe 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
Author(s) -
Arndt Borkhardt,
Stig E. Bojesen,
Oskar A. Haas,
Uta Fuchs,
Dominique Bartelheimer,
Ivan F. Lončarević,
Rainer M. Bohle,
Jochen Harbott,
Reinald Repp,
Ulrich Jaeger,
Susanne Viehmann,
Traudl Henn,
Petra Korth,
Dirk Scharr,
F. Lampert
Publication year - 2000
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.150079597
Subject(s) - biology , juvenile myelomonocytic leukemia , gene , genetics , allele , rhoa , tumor suppressor gene , ras superfamily , complementary dna , point mutation , null allele , gene family , mutation , signal transduction , carcinogenesis , gene expression , haematopoiesis , biochemistry , stem cell , gtp' , enzyme
We have isolated the humanGRAF gene (for GTPase regulator associated with the focal adhesion kinase pp125FAK ). This gene was fused withMLL 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 chickenGRAF gene that functions as a GAP of RhoAin vivo and is thus a critical component of the integrin signaling transduction pathway. The particular position of the humanGRAF 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 secondGRAF allele in one patient. In two additional patients we found an insertion of 52 or 74 bp within theGRAF 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 theGRAF gene may be instrumental in the development and progression of hematopoeitic disorders with a del(5q).