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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  (CBFbeta )-Smooth-Muscle Myosin Heavy Chain Sequesters CBFalpha 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 gene encodes a chimeric protein involving the core binding factor beta  (CBFbeta ) and the smooth-muscle myosin heavy chain (SMMHC). Mouse model studies suggest that this chimeric protein CBFbeta -SMMHC dominantly suppresses the function of CBF, a heterodimeric transcription factor composed of DNA binding subunits (CBFalpha 1 to 3) and a non-DNA binding subunit (CBFbeta ). This dominant suppression results in the blockage of hematopoiesis in mice and presumably contributes to leukemogenesis. We used transient-transfection assays, in combination with immunofluorescence and green fluorescent protein-tagged proteins, to monitor subcellular localization of CBFbeta -SMMHC, CBFbeta , and CBFalpha 2 (also known as AML1 or PEBP2alpha B). When expressed individually, CBFalpha 2 was located in the nuclei of transfected cells, whereas CBFbeta was distributed throughout the cell. On the other hand, CBFbeta -SMMHC formed filament-like structures that colocalized with actin filaments. Upon cotransfection, CBFalpha 2 was able to drive localization of CBFbeta into the nucleus in a dose-dependent manner. In contrast, CBFalpha 2 colocalized with CBFbeta -SMMHC along the filaments instead of localizing to the nucleus. Deletion of the CBFalpha -interacting domain within CBFbeta -SMMHC abolished this CBFalpha 2 sequestration, whereas truncation of the C-terminal-end SMMHC domain led to nuclear localization of CBFbeta -SMMHC when coexpressed with CBFalpha 2. CBFalpha 2 sequestration by CBFbeta -SMMHC was further confirmed in vivo in a knock-in mouse model. These observations suggest that CBFbeta -SMMHC plays a dominant negative role by sequestering CBFalpha 2 into cytoskeletal filaments and aggregates, thereby disrupting CBFalpha 2-mediated regulation of gene expression.

* 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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