CBFbeta is critical for AML1-ETO and TEL-AML1 activity.

Abstract

AML1-ETO and TEL-AML1 are chimeric proteins resulting from the t(8;21)(q22;q22) in acute myeloid leukemia, and the t(12;21)(p13;q22) in pre-B-cell leukemia, respectively. The Runt domain of AML1 in both proteins mediates DNA binding and heterodimerization with the core binding factor beta (CBFbeta) subunit. To determine whether CBFbeta is required for AML1-ETO and TEL-AML1 activity, we introduced amino acid substitutions into the Runt domain that disrupt heterodimerization with CBFbeta but not DNA binding. We show that CBFbeta contributes to AML1-ETO's inhibition of granulocyte differentiation, is essential for its ability to enhance the clonogenic potential of primary mouse bone marrow cells, and is indispensable for its cooperativity with the activated receptor tyrosine kinase TEL-PDGFbetaR in generating acute myeloid leukemia in mice. Similarly, CBFbeta is essential for TEL-AML1's ability to promote self-renewal of B cell precursors in vitro. These studies validate the Runt domain/CBFbeta interaction as a therapeutic target in core binding factor leukemias.

• Authors: Liya Roudaia, Matthew D Cheney, Ekaterina Manuylova, Wei Chen, Michelle Morrow, Sangho Park, Chung-Tsai Lee, Prabhjot Kaur, Owen Williams, John H Bushweller, Nancy A Speck
• Journal: Blood (Blood) Vol. 113 Issue 13 Pg. 3070-9 (Mar 26 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19179469 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• AML1-ETO fusion protein, human
• CBFB protein, human
• Core Binding Factor Alpha 2 Subunit
• Core Binding Factor beta Subunit
• Oncogene Proteins, Fusion
• RUNX1 Translocation Partner 1 Protein
• TEL-AML1 fusion protein

Topics

• Animals
• Cell Differentiation (genetics)
• Cell Proliferation
• Core Binding Factor Alpha 2 Subunit (genetics, physiology)
• Core Binding Factor beta Subunit (chemistry, genetics, metabolism, physiology)
• Granulocytes (metabolism, physiology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Models, Biological
• Models, Molecular
• Mutation (physiology)
• NIH 3T3 Cells
• Oncogene Proteins, Fusion (genetics, physiology)
• Protein Binding
• Protein Structure, Tertiary (genetics, physiology)
• RUNX1 Translocation Partner 1 Protein
• Transfection