Proto-oncogene AF-4 (or FEL) is a product of a chromosomal aberration of the human gene AFF1, which is associated with acute leukemias. The fusion of AF-4 on chromosome band 4q21 with the mixed lineage leukemia (MLL or HRX) gene on 11q23 results in a MLL-AF-4 chimeric transcription factor in which AF-4 contributes transcriptional effector properties and requires cell-specific accessory factors. MLL is involved in several chromosomal translocations associated with acute myeloid and lymphoid leukemia. The MLL-AF-4 fusion protein is expressed in all normal hematopoietic cells. The expression of MLL-AF-4 influences the production of protein cyclin-dependent kinase inhibitor (CDKN1B), suggesting that inhibition of MLL-AF-4 expression may be a powerful and highly specific treatment of chemotherapy-resistant leukemia.