ATP-binding cassette (ABC), ATP-dependent transporters are a large superfamily of proteins that include the multidrug resistance proteins, P- glycoprotein and MRP (multidrug resistance protein). The ARA (anthracycline resistance-associated) gene that codes for a putative member of the ABC transporters has recently been cloned and shown to have high sequence homology to the gene for MRP. We have previously shown MRP to be deleted in a subset of inv(16) leukemic patients. The deletion of MRP was associated with an improved patient survival compared with inv(16) patients who did not have such a deletion. In this study, the ARA gene is mapped to 16p13.1, in the same physical interval as the inv(16) short-arm breakpoint. It is shown to be situated proximal to both MYH11, the gene involved in the primary breakpoint on the short arm of the inv(16), and MRP. A YAC clone has been isolated containing both MRP and ARA. FISH analysis of metaphase chromosomes from inv(16) patients has established the gene order as telomere-MYH11-MRP-ARA- centromere and demonstrated that both ARA and MRP are deleted in a subgroup of the inv(16) leukemias. ARA and MRP are both shown to he expressed in normal hematopoietic precursors including CD34+ cells. The mapping of ARA to this region and its homology to MRP raises questions about its potential role in the biology of the inv(16) leukemias.