Structure Of The Aml1-Eto Nhr3-Ka(Rii Alpha) Complex And Its Contribution To Aml1-Eto Activity

AML1-ETO is the chimeric protein product of t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the nervy homology region (NHR) 3 domain, which shares homology with A-kinase anchoring proteins and interacts with the regulatory subunit of type II cAMP-dependent protein kinase A (PKA(RII alpha)). We determined the solution structure of a complex between the AML1-ETO NHR3 domain and PKA(RII alpha). Based on this structure, a key residue in AML1-ETO for PKA(RII alpha) 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-PKA(RII alpha) protein interaction does not appear to significantly contribute to AML1-ETO's ability to induce leukemia. (c) 2010 Elsevier Ltd. All rights reserved.