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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-09-2781.
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Blood, 1 July 2003, Vol. 102, No. 1, pp. 7-16
PLENARY PAPERS
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, Jr
From the Oregon Health & Science University (OHSU) Cancer Institute, Portland; Department of Molecular and Medical Genetics, OHSU, Portland; Department of Medicine, OHSU, Portland; Department of Pediatrics, OHSU, Portland; Veterans Administration Medical Center, Portland, OR; Division of Genetics and Development, Guys, King's, and St Thomas' School of Medicine, London, United Kingdom; Department of Haematology, University College Hospital, Galway, Ireland; and Section of Hematology/Oncology, University of Chicago, IL.
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. (Blood. 2003;102: 7-16)
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