CBFbeta is critical for AML1-ETO and TEL-AML1 activity.
Blood
; 113(13): 3070-9, 2009 Mar 26.
Article
em En
| MEDLINE
| ID: mdl-19179469
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Fusão Oncogênica
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Subunidade alfa 2 de Fator de Ligação ao Core
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Subunidade beta de Fator de Ligação ao Core
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
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Male
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article