Abstract
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(RIIα)). We determined the solution structure of a complex between the AML1-ETO NHR3 domain and PKA(RIIα). Based on 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-PKA(RIIα) protein interaction does not appear to significantly contribute to AML1-ETO's ability to induce leukemia.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites / genetics
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Cell Differentiation
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Core Binding Factor Alpha 2 Subunit / chemistry
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Core Binding Factor Alpha 2 Subunit / genetics*
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Core Binding Factor Alpha 2 Subunit / metabolism
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Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / chemistry*
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Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / metabolism
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Humans
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Leukemia, Myeloid, Acute / etiology
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism*
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Mice
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Mutation
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Oncogene Proteins, Fusion / chemistry*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RUNX1 Translocation Partner 1 Protein
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Transcription Factors / chemistry
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Transcription Factors / genetics*
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Transcription Factors / metabolism
Substances
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Core Binding Factor Alpha 2 Subunit
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Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
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Oncogene Proteins, Fusion
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PRKAR2A protein, human
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Proto-Oncogene Proteins
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RUNX1 Translocation Partner 1 Protein
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RUNX1T1 protein, human
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Transcription Factors