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AC133 (CD133, human Prominin-1) is a cell-surface glycoprotein which is expressed on several types of stem cells, including hematopoietic stem cells and endothelial progenitor cells. AC133 is also expressed on acute and chronic myeloid leukemias, as well as lymphoblastic leukemias. AC133 expression is correlated with a poor prognosis in cases of leukemia; in addition, preliminary observations suggest that AC133 may define a population of leukemic stem cells. We previously identified and characterized the AC133 promoter region, and demonstrated that transcription of AC133 is driven by five alternative promoters in a tissue-dependent manner, resulting in the formation of multiple alternatively spliced isoforms. CD34+hematopoietic stem cells were found to utilize only one of the five promoters, AC133-P1. Furthermore, preliminary data suggest that hematopoietic stem cells express only one AC133 isoform. We identified four allelic variants in the AC133-P1 promoter, 250 bp upstream of the transcription initiation point, which differ by the number of short tandem repeats as well as by a single nucleotide polymorphism (SNP). One allele, (CAA)3CAG, is found in patients with AML, chloroma, and myeloma. Two different alleles, (CAA)4and (CAAAA)5, are found in cancer cell lines derived from AML, retinoblastoma, colon cancer, and sarcoma. One allele, (CAA)5, is found only in healthy human subjects. Our preliminary results show that these different alleles may affect the activity of the AC133-P1 promoter. These data might lay a foundation for testing a risk of susceptibility to AC133+leukemias. Additional investigations are required to establish the role of AC133 in emergence, development and survival of leukemias, as well as to explore the viability of AC133 as a primary therapeutic target in patients with aggressive AC133+leukemia.