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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-09-2781.
Submitted September 11, 2002
Accepted November 21, 2002
Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia
M William Lensch, Marc Tischkowitz, Tracy A Christianson, Carol A Reifsteck, S Ashley Speckhart, Petra M Jakobs, Michael E O'Dwyer, Susan B Olson, Michelle M Le Beau, Shirley V Hodgson, Christopher G Mathew, Richard A Larson, and Grover C Bagby*
Cancer Institute, Oregon Health and Science University, Portland, OR, USA
Department of Medicine, Oregon Health and Science University, Portland, OR, USA
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA
NW VA Cancer Research Center, Portland VA Medical Center, Portland, OR, USA
Department of Medical and Molecular Genetics, Guy's, King's and St. Thomas' School of Medicine, London, United Kingdom
Deparment of Haematology, University College Hospital, Galway, Ireland
Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
* Corresponding author; email: grover{at}ohsu.edu.
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 while 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 AML patients who do not have Fanconi anemia.
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