Structure of the AML1-ETO eTAFH domain–HEB peptide complex and its contribution to AML1-ETO activity

• Published in: Blood Vol. 113; no. 15; pp. 3558 - 3567
• Main Authors: Park, Sangho, Chen, Wei, Cierpicki, Tomasz, Tonelli, Marco, Cai, Xiongwei, Speck, Nancy A., Bushweller, John H.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 09.04.2009; Americain Society of Hematology; American Society of Hematology
• Series: Myeloid Neoplasia
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Cell Differentiation - immunology; Cell Division - immunology; Cells, Cultured; Chlorocebus aethiops; Chromosome aberrations; Core Binding Factor Alpha 2 Subunit - chemistry; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; COS Cells; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Granulocytes - cytology; Granulocytes - physiology; Hematologic and hematopoietic diseases; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Male; Medical genetics; Medical sciences; Mice; Mice, Inbred C57BL; Myeloid Neoplasia; Nuclear Magnetic Resonance, Biomolecular; Oncogene Proteins, Fusion - chemistry; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Protein Structure, Secondary; Protein Structure, Tertiary; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-myc - metabolism; STAT6 Transcription Factor - metabolism; Structure-Activity Relationship; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Chromosomal aberration; Abnormal chromosome C8; Hematology; Peptides; Abnormal chromosome; Abnormal chromosome G21; Structure; Biological activity; Hybrid gene; Chromosome translocation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-06-161307

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 eTAFH domain, which is homologous to several TATA binding protein–associated factors (TAFs) and interacts with E proteins (E2A and HEB). It has been proposed that AML1-ETO–mediated silencing of E protein function might be important for t(8;21) leukemogenesis. Here, we determined the solution structure of a complex between the AML1-ETO eTAFH domain and an interacting peptide from HEB. On the basis of the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair the ability of AML1-ETO to enhance the clonogenic capacity of primary mouse bone marrow cells and do not eliminate its ability to repress proliferation or granulocyte differentiation. Therefore, the eTAFH-E protein interaction appears to contribute relatively little to the activity of AML1-ETO.