Genetic reversion in an acute myelogenous leukemia cell line from a Fanconi anemia patient with biallelic mutations in BRCA2

Hideyuki Ikeda, Maiko Matsushita, Quinten Waisfisz, Akitoshi Kinoshita, Anneke B. Oostra, Aggie W.M. Nieuwint, Johan P. De Winter, Maureen E. Hoatlin, Yohko Kawai, Masao S. Sasaki, Alan D. D'Andrea, Yutaka Kawakami, Hans Joenje

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2688-2694
Number of pages7
JournalCancer Research
Issue number10
Publication statusPublished - 2003 May 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Genetic reversion in an acute myelogenous leukemia cell line from a Fanconi anemia patient with biallelic mutations in BRCA2'. Together they form a unique fingerprint.

Cite this