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

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)...

Full description

Saved in:
Bibliographic Details
Published in:Blood 2009-03, Vol.113 (13), p.3070-3079
Main Authors: Roudaia, Liya, Cheney, Matthew D, Manuylova, Ekaterina, Chen, Wei, Morrow, Michelle, Park, Sangho, Lee, Chung-Tsai, Kaur, Prabhjot, Williams, Owen, Bushweller, John H, Speck, Nancy A
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - genetics
Cell Proliferation
Core Binding Factor Alpha 2 Subunit - genetics
Core Binding Factor Alpha 2 Subunit - physiology
Core Binding Factor beta Subunit - chemistry
Core Binding Factor beta Subunit - genetics
Core Binding Factor beta Subunit - metabolism
Core Binding Factor beta Subunit - physiology
Granulocytes - metabolism
Granulocytes - physiology
Humans
Male
Mice
Mice, Inbred C57BL
Models, Biological
Models, Molecular
Mutation - physiology
NIH 3T3 Cells
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - physiology
Protein Binding
Protein Structure, Tertiary - genetics
Protein Structure, Tertiary - physiology
RUNX1 Translocation Partner 1 Protein
Transfection
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1528-0020
DOI:10.1182/blood-2008-03-147207