CBFβ is critical for AML1-ETO and TEL-AML1 activity
Copyright policy )CBFβ is critical for AML1-ETO and TEL-AML1 activity
AbstractAML1-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 β (CBFβ) subunit. To determine whether CBFβ is required for AML1-ETO and TEL-AML1 activity, we introduced amino acid substitutions into the Runt domain that disrupt heterodimerization with CBFβ but not DNA binding. We show that CBFβ 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-PDGFβR in generating acute myeloid leukemia in mice. Similarly, CBFβ is essential for TEL-AML1's ability to promote self-renewal of B cell precursors in vitro. These studies validate the Runt domain/CBFβ interaction as a therapeutic target in core binding factor leukemias.
- University of Pennsylvania United States
- University College London United Kingdom
- University of Virginia United States
- Dartmouth College United States
Male, Models, Molecular, Oncogene Proteins, Fusion, Cell Differentiation, Transfection, Models, Biological, Core Binding Factor beta Subunit, Protein Structure, Tertiary, Mice, Inbred C57BL, Mice, RUNX1 Translocation Partner 1 Protein, Core Binding Factor Alpha 2 Subunit, Mutation, NIH 3T3 Cells, Animals, Humans, Cell Proliferation, Granulocytes, Protein Binding
Male, Models, Molecular, Oncogene Proteins, Fusion, Cell Differentiation, Transfection, Models, Biological, Core Binding Factor beta Subunit, Protein Structure, Tertiary, Mice, Inbred C57BL, Mice, RUNX1 Translocation Partner 1 Protein, Core Binding Factor Alpha 2 Subunit, Mutation, NIH 3T3 Cells, Animals, Humans, Cell Proliferation, Granulocytes, Protein Binding
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