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Genetic Reversion in an Acute Myelogenous Leukemia Cell Line from a Fanconi Anemia Patient with Biallelic Mutations in BRCA2¹

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan [H. I., M. M., Y. Kawak.]; Department of Clinical Genetics and Human Genetics, VU University Medical Center 1081 BT, Amsterdam, the Netherlands [Q. W., A. B. O., A. W. M. N., J. P. d. W., H. J.]; Department of Pediatrics, Shizuoka Red Cross Hospital, Shizuoka 420-0853, Japan [A. K.]; Division of Molecular Medicine, Oregon Health and Science University, Portland, Oregon 97201 [M. E. H.]; Department of Laboratory Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan [Y. Kawai]; Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan [M. S. S.]; and Department of Pediatric Oncology, Dana Farber Cancer Institute, and Department of Pediatrics, Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 [A. D. D.]

A 2-year old boy was diagnosed with Fanconi anemia (FA) and acute myeloid leukemia (AML). A cell line (termed FA-AML1) was established from blast cells obtained after a second relapse after a successful bone marrow transplant. Histochemical and surface marker analysis confirmed that the cells were derived from the myeloid lineage. Cytogenetic analysis revealed multiple chromosomal aberrations, including a ring 7. Stable proliferation of the cultured cells was absolutely dependent on the presence of granulocyte macrophage colony-stimulating factor or interleukin 3. This is the first AML cell line successfully established from a FA patient. Remarkably, FA-AML1 cells appeared to lack the characteristic cellular FA phenotype, i.e., a hypersensitivity to growth inhibition and chromosomal breakage by the cross-linking agent mitomycin C. Genomic DNA from the patient showed biallelic mutations [8415G>T (K2729N)and 8732C>A (S2835STOP)] in the breast cancer susceptibility gene FANCD1/BRCA2 [N. Howlett et al., Science (Wash. DC), 297: 606–609, 2002]. In the AML cells, however, the 8732C>A nonsense mutation was changed into a missense mutation by a secondary alteration, 8731T>G, resulting in 2835E, which restored the open-reading frame of the gene and could explain the reverted phenotype of these cells. Loss of the FA phenotype by genetic correction of a FA gene mutation during AML progression may be a common late event in the pathogenesis of AML in FA patients, which may be treatment related. This finding suggests a novel mechanistic principle of tumor progression based on the genetic correction of an early caretaker gene defect.

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