Genetic reversion in an acute myelogenous leukemia cell line from a Fanconi anemia patient with biallelic mutations in BRCA2.
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.
Ikeda
Hideyuki
H
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
Matsushita
Maiko
M
Waisfisz
Quinten
Q
Kinoshita
Akitoshi
A
Oostra
Anneke B
AB
Nieuwint
Aggie W M
AW
De Winter
Johan P
JP
Hoatlin
Maureen E
ME
Kawai
Yohko
Y
Sasaki
Masao S
MS
D'Andrea
Alan D
AD
Kawakami
Yutaka
Y
Joenje
Hans
H
D000483:Alleles; D015703:Antigens, CD / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D002675:Child, Preschool; D005199:Fanconi Anemia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D024522:Genes, BRCA2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor