doi: 10.1006/scdb.2000.0181, available online at http://www.idealibrary.com on seminars in CELL & DEVELOPMENTAL BIOLOGY, Vol. 11, 2000: pp. 361–368 Function of CBFβ /Bro proteins N. Adya, L. H. Castilla and P. P. Liu Mammalian core binding factor β (CBFβ ) and Drosophila Brother (Bro) and Big-brother (Bgb) proteins are transcrip- tion factors that dimerize with mammalian Runx and Drosophila Runt and Lozenge proteins and augment their DNA binding affinity and transcriptional potency. CBFβ is essential for development and sustenance of definitive hematopoiesis during mouse embryogenesis. Bro and Bgb are required for Runt/Lozenge functions in Drosophila development. CBFβ contributes to leukemogenesis since the CBFB gene is specifically and consistently mutated by a chromosome 16 inversion found in patients with acute myeloid leukemia subtype M4Eo. The ubiquitous expression pattern of the CBFB gene suggests that it may play important roles in many other organ systems. Key words: Cbfb / hematopoiesis / Pebp2 / Bro / Bgb / translocation / transcription c  2000 Academic Press Introduction CBF or PEBP2 was originally identified as a sequence specific DNA-binding protein that activates tran- scription from enhancers of two different mouse viruses: Moloney murine leukemia virus (MLV), a type C retrovirus 1 , and polyoma virus, a DNA tumor virus. 2, 3 Molecular studies demonstrated that CBF/PEBP2 is a heterodimer, composed of a β -subunit (CBFβ /PEBP2β ) and an α-subunit (CBFα/PEBP2α, now known by a unified name Runx). 4–6 Two CBFB-related Drosophila genes, Brother [acronym for Beta for r unt and others (Bro)] From the Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH Building 49, Room 3B19, 49 Convent Drive, Bethesda, MD 20892, USA. c 2000 Academic Press 1084–9521 / 00 / 000361+ 08 / $35.00/0 / 0 and the slightly larger Big-brother (Bgb), have also been isolated, which encode proteins that interact with Runt and Lozenge. 7 Unrelated to Runx/Runt proteins at the sequence level, CBFβ /Brother pro- teins enhance DNA binding affinity of Runx/Runt proteins and are required for the in vivo functions of at least some Runx/Runt proteins. CBFB is also important for leukemogenesis. Here we briefly review recent studies on CBFB and Brother genes. Gene structure and sequence analysis Only a single gene encoding CBFβ has been iden- tified in mammals (CBFB in human and Cbfb in mouse), unlike the CBFα subunit that consists of a family of three related genes. 5, 6, 8 The human CBFB gene maps to chromosome 16 q22 whereas the mouse Cbfb gene maps to chromosome 8. Both human and mouse CBFB genes contain six exons and are alternatively spliced to yield four protein isoforms (Figure 1). 5, 6, 9 CBFβ (187) and CBFβ (182) isoforms are generated by two different splice donors (31 nucleotides apart) at the 3 ′ end of exon 5. Consequently, exon 6 is spliced to exon 5 in two different reading frames, generating protein isoforms that diverge from amino acid 166 at their C-termini. Cbfβ (148) and Cbfβ (155) isoforms are generated by splicing skipping exons 3 and 5, respectively. The human CBFB gene has a long 3 ′ untranslated region (about 2.3 kb long), which is rich in AT nucleotides that may play some role in mRNA degradation. 10, 11 Two homologues of CBFβ exist in Drosophila, Bro and Bgb. 7 Comparison between cDNA and genomic DNA sequences reveals that both genes are devoid of any introns. Both Bro and Bgb genes map to the left arm of chromosome 3 (at position 62A10) and they are only 7 kb apart in a tandem orientation (with Bgb upstream), suggesting that they arose from a recent gene duplication in the Drosophila genome. 361