Core-binding factor: A central player in hematopoiesis and leukemia

Consistent chromosomal rearrangements are found in a large number of hemato poietic tumors, In many cases, these rearrangements disrupt genes whose nor mal function is required for the proper development of blood cells, Excelle nt examples are the chromosomal rearrangements t(8;21)(q22;q22), t(12;21)(p 13;q22), and inv(16)(p13q22) that disrupt two of the genes encoding a small family of heterodimeric transcription factors, core-binding factors (CBFs) , CBFs consist of a DNA-binding CBF alpha subunit and a non-DNA-binding CBF beta subunit, The t(8;21), associated with de novo acute myeloid leukemias , disrupts the CBFA2 (AML1) gene, which encodes a DNA-binding CBF alpha sub unit. The t(12;21), the most common translocation in pediatric acute lympho cytic leukemias, also disrupts CBFA2. The CBFB gene, which encodes the non- DNA-binding subunit of the CBFs, is disrupted by the inv(16) in de novo acu te myeloid leukemias. All chromosomal rearrangements involving the CBFA2 an d CBFB genes create chimeric proteins, two of which have been unequivocally demonstrated to function as transdominant negative inhibitors of CBF funct ion. Both the Cbfa2 and Cbfb genes are essential for normal hematopoiesis in mic e, because homozygous disruption of either gene blocks definitive hematopoi esis. Recent data suggest that Cbfa2 and Cbfb are required for the emergenc e of definitive hematopoietic stem cells in the embryo from a putative defi nitive hemangioblast precursor. The transdominant negative inhibitor of CBF created by the inv(16), when present from the beginning of embryogenesis, also blocks the emergence of definitive hematopoietic cells in the embryo. On the other hand, chromosomal translocations involving the CBFA2 and CBFB genes in leukemias block hematopoiesis at later steps. This may reflect a d ifference in the timing at which translocations are acquired in the leukemi as, which presumably is subsequent to emergence of the definitive hematopoi etic stem cell. The cumulative data suggest that although the earliest requ irement for Cbfa2 and Cbfb is for emergence of definitive hematopoietic ste m cells, both genes are also required at later stages in the differentiatio n of some hematopoietic lineages.