title: Heterozygous deletion of the PU.1 locus in human AML.
abstract: The transcription factor PU.1 is essential for myeloid development. Targeted disruption of an upstream regulatory element (URE) decreases PU.1 expression by 80% and leads to acute myeloid leukemia (AML) in mice. Here, we sequenced the URE sequences of PU.1 in 120 AML patients. Four polymorphisms (single nucleotide polymorphisms [SNPs]) in the URE were observed, with homozygosity in all SNPs in 37 patients. Among them, we compared samples at diagnosis and remission, and one patient with cytogenetically normal acute myeloid leukemia M2 was identified with heterozygosity in 3 of the SNPs in the URE at remission. Loss of heterozygosity was further found in this patient at 2 polymorphic sites in the 5' promoter region and in 2 intronic sites flanking exon 4, thus suggesting loss of heterozygosity covering at least 40 kb of the PU.1 locus. Consistently, PU.1 expression in this patient was markedly reduced. Our study suggests that heterozygous deletion of the PU.1 locus can be associated with human AML.
authors.affiliation: Department of Internal Medicine and Clinical Research, University Hospital, and University of Bern, Bern, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bonadies
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.forename: Beatrice U
authors.initials: BU
authors.lastname: Mueller
mesh_terms: D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D017384:Sequence Deletion; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1