title: Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia.
abstract: Myelodysplastic and leukemic stem cell clones that evolve in children and adults with Fanconi anemia universally bear complex cytogenetic abnormalities. The abnormalities are generally recurring deletions or chromosomal loss and involve precisely the same chromosomes with the same frequency as has been described in marrow cells from patients with secondary acute leukemia induced by alkylating agents. Reasoning that acquired Fanconi anemia protein dysfunction might contribute to cytogenetic instability in secondary acute myelogenous leukemia (AML) cells, we analyzed leukemic cells bearing characteristic complex cytogenetic defects obtained from a 68-year-old man whose lymphoblasts showed no evidence of Fanconi anemia. Unlike the lymphoblasts, this myeloid leukemia cell line (UoC-M1) was hypersensitive to mitomycin-C (MMC) and diepoxybutane (DEB) and exhibited a marked decrease in nuclear FANCA, FANCG, and FANCD2-L. Retroviral transduction of FANCA significantly reduced MMC sensitivity but FANCF, FANCG, and FANCC did not. Overexpression of FANCA restored levels of both FANCA and FANCG, whereas overexpression of FANCG or FANCC did not restore FANCA levels. The molecular mass of cytoplasmic FANCA, FANCG, FANCC, and nuclear FANCD2 were normal. All exons of FANCA and FANCG were sequenced, and no mutations were found. We conclude that perturbations of as yet unidentified factors that govern the binding activity or intracellular localization of FANCA may promote cytogenetic instability and clonal progression in patients with AML who do not have Fanconi anemia.
authors.affiliation: OHSU Cancer Institute, CR145, Hatfield Research Center, 3181 SW Sam Jackson Park Rd, Portland, OR 97201, USA.
authors.forename: M William
authors.initials: MW
authors.lastname: Lensch
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Christianson
authors.forename: Carol A
authors.initials: CA
authors.lastname: Reifsteck
authors.forename: S Ashley
authors.initials: SA
authors.lastname: Speckhart
authors.forename: Petra M
authors.initials: PM
authors.lastname: Jakobs
authors.forename: Michael E
authors.initials: ME
authors.lastname: O'Dwyer
authors.forename: Susan B
authors.initials: SB
authors.lastname: Olson
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Shirley V
authors.initials: SV
authors.lastname: Hodgson
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
mesh_terms: D000368:Aged; D000477:Alkylating Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002869:Chromosome Aberrations / Q000139:chemically induced; D002999:Clone Cells; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D008297:Male; D016685:Mitomycin / Q000494:pharmacology; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000032:analysis; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000477:Alkylating Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; C497651:FANCC protein, human; C499905:FANCD2 protein, human; C499909:FANCG protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016685:Mitomycin