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) 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.
Roudaia
Liya
L
Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA.
Cheney
Matthew D
MD
Manuylova
Ekaterina
E
Chen
Wei
W
Morrow
Michelle
M
Park
Sangho
S
Lee
Chung-Tsai
CT
Kaur
Prabhjot
P
Williams
Owen
O
Bushweller
John H
JH
Speck
Nancy A
NA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000502:physiology*; D050658:Core Binding Factor beta Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006098:Granulocytes / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D000075142:RUNX1 Translocation Partner 1 Protein; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C107844:AML1-ETO fusion protein, human; C493692:CBFB protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein