Structure of the AML1-ETO Nervy Domain - PKA(RIIa) complex and its contribution to AML1-ETO activity

AML1-ETO is the chimeric protein product of the t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the Nervy Homology Region 3 (NHR3) domain, which shares homology with A-Kinase Anchoring Proteins (AKAPs) and interacts with the regulatory subunit of type II cAMP-dependent Protein Kinase (PKA (RIIα)). We determined the solution structure of a complex between the AML1-ETO NHR3 domain and PKA (RIIα). On the basis of this structure, a key residue in AML1-ETO for PKA (RIIα) association was mutated. This mutation did not disrupt AML1-ETO’s ability to enhance the clonogenic capacity of primary mouse bone marrow cells or its ability to repress proliferation or granulocyte differentiation. Introduction of the mutation into AML1-ETO had minimal impact on in vivo leukemogenesis. Therefore, the NHR3 domain/PKA(RIIα) protein interaction does not appear to significantly contribute to AML1-ETO’s ability to induce leukemia.