Acute myeloid leukemia occurs in approximately 3.5 per 100,000 individuals each year. CBF-AML accounts for 12 to 15 percent of acute myeloid leukemia cases in adults.

CBF-AML is associated with chromosomal rearrangements between chromosome 8 and chromosome 21 and within chromosome 16. The rearrangements involve the RUNX1, RUNX1T1, CBFB, and MYH11 genes. Two of these genes, RUNX1 and CBFB, provide instructions for making the two pieces of a protein complex known as core binding factor (CBF). CBF attaches to certain regions of DNA and turns on genes that help control the development of blood cells (hematopoiesis). In particular, it plays an important role in development of hematopoietic stem cells. Chromosomal rearrangements involving the RUNX1 or CBFB gene alter CBF, leading to leukemia.

In CBF-AML, the RUNX1 gene is affected by a type of genetic rearrangement known as a translocation; in this type of change, pieces of DNA from two chromosomes break off and are interchanged. The most common translocation in this condition, called t(8;21), fuses a part of the RUNX1 gene on chromosome 21 with part of the RUNX1T1 gene (also known as ETO) on chromosome 8. The combination of these genes leads to production of the RUNX1-ETO fusion protein. This fusion protein is able to form CBF and attach to DNA, like the normal RUNX1 protein. However, because the function of the protein produced from the normal RUNX1T1 gene is to block gene activity, the abnormal CBF turns genes off instead of turning them on.

Other genetic rearrangements associated with CBF-AML alter the CBFB gene. One such rearrangement, called an inversion, involves breakage of a chromosome in two places; the resulting piece of DNA is reversed and reinserted into the chromosome. The inversion involved in CBF-AML (written as inv(16)) leads to the fusion of two genes on chromosome 16, CBFB and MYH11. Less commonly, a translocation involving chromosome 16, written as t(16;16), leads to the fusion of the same two genes. The protein produced from these genetic rearrangements is called CBFβ-MYH11. The fusion protein can form CBF, but it is thought that the presence of the MYH11 portion of the fusion protein prevents CBF from binding to DNA, impairing its ability to control gene activity. Alternatively, the MYH11 portion may interact with other proteins that prevent CBF from controlling gene activity.

The change in gene activity caused by alteration of CBF blocks the maturation (differentiation) of blood cells and leads to the production of abnormal myeloid blasts. However, a chromosomal rearrangement alone is usually not enough to cause leukemia; one or more additional genetic changes are needed for cancer to develop. The additional changes likely cause the immature cells to grow and divide uncontrollably, leading to the excess of myeloid blasts characteristic of CBF-AML.