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

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 un ique t(5;11)(q31;q23) that occurred in an infant with juvenile myelomonocyt ic leukemia. GRAF encodes a member of the Rho family of the GTPase-activati ng protein (CAP) family. On the protein level, it is 90% homologous to the recently described chicken GRAF gene that functions as a GAP of RhoA in viv o and is thus a critical component of the integrin signaling transduction p athway. The particular position of the human GRAF gene at 5q31 and the prop osed antiproliferative and tumor suppressor properties of its avian homolog ue suggest that it also might be pathogenetically relevant for hematologic malignancies with deletions of 5q. To investigate this possibility, we sequ enced 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 G RAF 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 f ollowed by a premature stop codon, GRAF maps outside the previously defined commonly deleted 5q31 region. Nevertheless, inactivation of both alleles i n at least some cases suggests that deletions and mutations of the GRAF gen e may be instrumental in the development and progression of hematopoeitic d isorders with a del(5q).