The N-ras oncogene and acute myeloid leukemia

Abstract

Members of the ras gene family (N-ras, H-ras and K-ras) are highly conserved and encode similar 21kd guanosine nucleotide binding proteins (p21) located on the cytoplasmic aspect of the cell membrane. Ras p21 proteins are thought to participate in the transduction of extracellular signals (eg. from growth factors) to the cell nucleus, and appear to play a role in cell proliferation and differentiation. Signal transduction is terminated by interaction with GAP which stimulates the intrinsic GTPase activity of p21. Ras genes acquire transforming properties when point mutations occur at critical codons, resulting in amino acid substitutions in ras proteins. GAP is unable to augment the GTPase activity of mutant p21 proteins which then function constitutively in the absence of extracellular signals. Point mutations involving codons 12, 13 and 61 of N-ras occur in 20-50% of patients with AML. Detection systems include allele specific oligohybridisation, NLH/3T3 transfection, and a new technique developed in our unit known as allele specific restriction analysis. Mutations in H-ras and K-ras occur less frequently, and double mutations are relatively common. N-ras mutations are also found in MDS and ALL, but are rare in other hematological malignancies. Mutations are generally undetectable during remission of AML, and differential patterns at presentation and relapse indicate that N-ras mutations are not an early event in leukemogenesis. The prognostic significance of N-ras mutations and increased expression is unclear in AML, but mutations may predict progression of MDS to leukemia, and may predict early relapse in ALL. The N-ras gene promoter is also of interest, and we are examining its structure-function relationships.