Disease relevance of Cbfb

• Core-binding factor beta (CBFbeta, also called polyomavirus enhancer binding protein 2beta (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans [1].
• In contrast, the CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein generated by the inv(16) associated with acute myeloid leukemias (M4Eo) cannot rescue definitive hematopoiesis by Cbfb-deficient ES cells [2].
• However, Runx2-I/Cbfb and Runx2-II/Cbfb double transgenic mice had enhanced inhibition of osteoblast maturation, resulting in similar severity of osteopenia and fragility, although the latter mice had less osteocytes [3].
• CBFbeta-SMMHC significantly increased the development of acute leukemias from marrow lacking the overlapping p16p19 genes, based on analysis of Kaplan-Meier event-time distributions [4].
• These results show that PEBP2betaMYH11 can impair neutrophil development and provide evidence that alterations of Pebp2 can contribute to the genesis of myelodysplasia [5].

High impact information on Cbfb

• To investigate this issue, we rescued hematopoiesis of Cbfb(-/-) mice by introducing Cbfb using the Gata1 promoter [1].
• The core-binding factor beta subunit is required for bone formation and hematopoietic maturation [6].
• Here we show that by providing Cbfbeta function in endothelial cells and hematopoietic progenitors we can rescue fetal liver hematopoiesis in Cbfbeta-deficient embryos [6].
• The fusion allele maintains sufficient function in hematopoietic cells to bypass the early embryonic lethality, and identifies a new role for Cbfb in bone development [7].
• Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta [8].

Chemical compound and disease context of Cbfb

• Polyomavirus enhancer binding protein, PEBP2 (PEA2), is a heterodimer of two distinct subunits, alpha and beta, of which the former directly binds to DNA and the latter acts auxiliary to enhance the DNA binding [9].

Biological context of Cbfb

• The rescued Cbfb(-/-) mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation [1].
• Here we demonstrate that homozygous mutation of the Cbfb gene results in the same phenotype [10].
• Definitive hematopoiesis is restored by ectopic expression of full-length Cbfb transgenes, as well as by a transgene encoding only the heterodimerization domain of CBFbeta [2].
• Role of Cbfb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene Cbfb-MYH11 [11].
• Cells transformed by CBF beta-SMMHC lack normal CBF-DNA complexes and have decreased levels of transactivation [12].

Anatomical context of Cbfb

• This population of stem cells and progenitors was not present in mouse embryos heterozygous for the Cbfb-MYH11 knock-in gene [11].
• Homozygous disruption of either the Runx1 or Cbfb gene in mice results in embryonic lethality at midgestation due to hemorrhaging in the central nervous system, and severely impairs fetal liver hematopoiesis [2].
• Core binding factor beta-smooth muscle myosin heavy chain chimeric protein involved in acute myeloid leukemia forms unusual nuclear rod-like structures in transformed NIH 3T3 cells [13].
• Normal CBFbeta showed an unexpected perinuclear pattern consistent with primary localization in the Golgi complex [13].
• Co-precipitation analysis of transgenic thymus revealed high levels of Cbfa1 protein in an abundant complex containing the binding cofactor Cbfb [14].

Associations of Cbfb with chemical compounds

• Exposing mice transplanted with CBFbeta-SMMHC-transduced cells to a mutagen, ethylnitrosourea, markedly accelerated leukemogenesis compared to expressing CBFbeta-SMMHC with loss of p16p19, indicating the need for multiple "hits" for transformation [4].
• Cloning and expression pattern of a novel PEBP2 beta-binding protein (charged amino acid rich leucine zipper-1[Crl-1]) in the mouse [15].
• We have developed Ba/F3 cell lines in which zinc regulates CBFbeta-SMMHC expression and 4-hydroxytamoxifen activates c-Myc-ER [16].
• Here we report an alanine-scanning mutagenesis study of the Runt domain that targeted amino acids identified by structural studies to reside at the DNA or CBF beta interface, as well as amino acids mutated in human disease [17].
• Site-directed mutagenesis of the amino acid residue 72, a highly conserved cysteine in the runt homology domain of AML1, to serine almost completely abolished DNA binding without altering the interaction with PEBP2beta/CBFbeta [18].

Physical interactions of Cbfb

• These mutations result in the expression of fusion proteins that act dominant-negatively to suppress the normal function of the Runt-related transcription factor 1 (RUNX)/core binding factor beta (CBFbeta) complexes [19].

Other interactions of Cbfb

• The models that have been developed should prove to be of value for defining the range of mutations that can cooperate with AML1/CBFbeta fusion proteins, and for assessing novel therapies targeted toward the pathways that are altered by the expression of these fusion proteins [20].
• These findings show that this novel PEBP2 beta-interacting protein is expressed mainly in subsets of neuronal cells, suggesting that Crl-1 plays some role in the developing mouse brain [15].
• The cDNA isolated from mouse fibroblasts encoding the alpha-subunit of polyomavirus enhancer binding protein 2 (PEBP2/PEA2) revealed that it also has a runt homology region (E. Ogawa et al., submitted) [21].
• Chromosomal translocations involving the genes encoding the alpha and beta subunits of the Pebp2/Cbf transcription factor have been associated with human acute myeloid leukemia and the preleukemic condition, myelodysplasia [5].
• To investigate these effects on hematopoiesis, we expressed CBF beta-SMMHC from the metallothionein promoter, in both 32D cl3 myeloid cells and Ba/F3 B-lymphoid cells [22].

Analytical, diagnostic and therapeutic context of Cbfb

• Subcellular localizations of the wild-type CBFbeta and the CBFbeta-SMMHC fusion protein were determined by immunofluorescence of NIH 3T3 cells that overexpress wild-type or fusion protein [13].
• On luciferase and electrophoretic mobility shift assays, Runx2-I was less active than Runx2-II in the absence of Cbfb, but the two Runx2 isoforms had similar activity levels in the presence of Cbfb [3].
• Molecular cloning and characterization of PEBP2 beta, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2 alpha [9].
• To examine the expression of the PEBP2beta/CBFbeta protein in vivo, we carried out immunohistochemistry using the tissues from adult mice as well as embryos [23].
• Crystallization and preliminary X-ray analyses of quaternary, ternary and binary protein-DNA complexes with involvement of AML1/Runx-1/CBFalpha Runt domain, CBFbeta and the C/EBPbeta bZip region [24].

References