Fhit-deficient hematopoietic stem cells survive hydroquinone exposure carrying precancerous changes

Hideshi Ishii, Koshi Mimori, Kazuhiro Ishikawa, Hiroshi Okumura, Flavia Pichiorri, Teresa Druck, Hiroshi Inoue, Andrea Vecchione, Toshiyuki Saito, Masaki Mori, Kay Huebner

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The fragile FHIT gene is among the first targets of DNA damage in preneoplastic lesions, and recent studies have shown that Fhit protein is involved in surveillance of genome integrity and checkpoint response after genotoxin exposure. We now find that Fhit-deficient hematopoietic cells, exposed to the genotoxin hydroquinone, are resistant to the suppression of stem cell in vitro colony formation observed with wild-type (Wt) hematopoietic cells. In vivo-transplanted, hydroquinone-exposed, Fhit-deficient bone marrow cells also escaped the bone marrow suppression exhibited by Wt-transplanted bone marrow. Comparative immunohistochemical analyses of bone marrow transplants showed relative absence of Bax in Fhit-deficient bone marrow, suggesting insensitivity to apoptosis; assessment of DNA damage showed that occurrence of the oxidized base 8-hydroxyguanosine, a marker of DNA damage, was also reduced in Fhit-deficient bone marrow, as was production of intracellular reactive oxygen species. Treatment with the antioxidant N-acetyl-L-cysteine relieved hydroquinone-induced suppression of colony formation by Wt hematopoietic cells, suggesting that the decreased oxidative damage to Fhit-deficient cells, relative to Wt hematopoietic cells, accounts for the survival advantage of Fhit-deficient bone marrow. Homology-dependent recombination repair predominated in Fhit-deficient cells, although not error-free repair, as indicated by a higher incidence of 6-thioguanine-resistant colonies. Tissues of hydroquinone-exposed Fhit-deficient bone marrow-transplanted mice exhibited preneoplastic alterations, including accumulation of histone H2AX-positive DNA damage. The results indicate that reduced oxidative stress, coupled with efficient but not error-free DNA damage repair, allows unscheduled long-term survival of genotoxin-exposed Fhit-deficient hematopoietic stem cells carrying deleterious mutations.

ジャーナルCancer Research
出版物ステータス出版済み - 5 15 2008

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

フィンガープリント Fhit-deficient hematopoietic stem cells survive hydroquinone exposure carrying precancerous changes' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

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    Ishii, H., Mimori, K., Ishikawa, K., Okumura, H., Pichiorri, F., Druck, T., Inoue, H., Vecchione, A., Saito, T., Mori, M., & Huebner, K. (2008). Fhit-deficient hematopoietic stem cells survive hydroquinone exposure carrying precancerous changes. Cancer Research, 68(10), 3662-3670. https://doi.org/10.1158/0008-5472.CAN-07-5687