The Leukemic Protein Core Binding Factor beta  (CBFbeta )-Smooth-Muscle Myosin Heavy Chain Sequesters CBFalpha 2 into Cytoskeletal Filaments and Aggregates

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Molecular and Cellular Biology, December 1998, p. 7432-7443, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Leukemic Protein Core Binding Factor $beta$ (CBF $beta$ )-Smooth-Muscle Myosin Heavy Chain Sequesters CBF $alpha$ 2 into Cytoskeletal Filaments and Aggregates

Neeraj Adya,¹ Terryl Stacy,² Nancy A. Speck,² and Pu Paul Liu¹^,^*

Oncogenesis and Development Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892,¹ and Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755²

Received 31 March 1998/Returned for modification 19 May 1998/Accepted 10 September 1998

The fusion gene CBFB-MYH11 is generated by the chromosome 16 inversion associated with acute myeloid leukemias. This geneencodes a chimeric protein involving the core binding factor $beta$ (CBF $beta$ ) and the smooth-muscle myosin heavy chain (SMMHC). Mousemodel studies suggest that this chimeric protein CBF $beta$ -SMMHC dominantlysuppresses the function of CBF, a heterodimeric transcriptionfactor composed of DNA binding subunits (CBF $alpha$ 1 to 3) and a non-DNAbinding subunit (CBF $beta$ ). This dominant suppression results in theblockage of hematopoiesis in mice and presumably contributes toleukemogenesis. We used transient-transfection assays, in combinationwith immunofluorescence and green fluorescent protein-tagged proteins,to monitor subcellular localization of CBF $beta$ -SMMHC, CBF $beta$ , and CBF $alpha$ 2(also known as AML1 or PEBP2 $alpha$ B). When expressed individually,CBF $alpha$ 2 was located in the nuclei of transfected cells, whereasCBF $beta$ was distributed throughout the cell. On the other hand, CBF $beta$ -SMMHCformed filament-like structures that colocalized with actin filaments.Upon cotransfection, CBF $alpha$ 2 was able to drive localization of CBF $beta$ into the nucleus in a dose-dependent manner. In contrast, CBF $alpha$ 2colocalized with CBF $beta$ -SMMHC along the filaments instead of localizingto the nucleus. Deletion of the CBF $alpha$ -interacting domain withinCBF $beta$ -SMMHC abolished this CBF $alpha$ 2 sequestration, whereas truncationof the C-terminal-end SMMHC domain led to nuclear localizationof CBF $beta$ -SMMHC when coexpressed with CBF $alpha$ 2. CBF $alpha$ 2 sequestrationby CBF $beta$ -SMMHC was further confirmed in vivo in a knock-in mousemodel. These observations suggest that CBF $beta$ -SMMHC plays a dominantnegative role by sequestering CBF $alpha$ 2 into cytoskeletal filamentsand aggregates, thereby disrupting CBF $alpha$ 2-mediated regulation ofgeneexpression.

^* Corresponding author. Mailing address: NHGRI, National Institutes of Health, 49 Convent Dr., Room 3C28, Bethesda, MD 20892.Phone: (301) 402-2529. Fax: (301) 402-4929. E-mail: pliu{at}nhgri.nih.gov.

Molecular and Cellular Biology, December 1998, p. 7432-7443, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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The Leukemic Protein Core Binding Factor (CBF)-Smooth-Muscle Myosin Heavy Chain Sequesters CBF2 into Cytoskeletal Filaments and Aggregates

The Leukemic Protein Core Binding Factor $beta$ (CBF $beta$ )-Smooth-Muscle Myosin Heavy Chain Sequesters CBF $alpha$ 2 into Cytoskeletal Filaments and Aggregates