title: Heritable polymorphism predisposes to high BAALC expression in acute myeloid leukemia.
abstract: Overexpression of the brain and acute leukemia, cytoplasmic (BAALC) gene is implicated in myeloid leukemogenesis and associated with poor outcome in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. Additionally, high BAALC expression occurs in glioblastoma, melanoma, and childhood gastrointestinal stroma tumors, suggesting an oncogenic role for BAALC. However, the mechanisms underlying the deregulated expression are unknown. We hypothesized that a common heritable genetic feature located in cis might account for overexpression of BAALC in an allele-specific manner. By sequencing the genomic region of BAALC we identified nine informative single nucleotide polymorphisms (SNPs) and tested them for a possible association with BAALC expression levels. We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. The association of high BAALC expression with the T allele and its correlations with RUNX1 expresser status are shown in vivo in a test set (n = 253) and validation set (n = 105) of samples from cytogenetically normal AML patients from different populations. Thus, we identify a heritable genomic feature predisposing to overexpression of an oncogene, thereby possibly leading to enhanced AML leukemogenesis. Our findings further suggest that genomic variants might become useful tools in the practice of personalized medicine.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leffel
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Tanner
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001665:Binding Sites; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: C442828:BAALC protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D009363:Neoplasm Proteins; C493728:RUNX1 protein, human