NF-KappaB family proteins participates in multiple steps of hematopoiesis through elimination of reactive oxygen species

doi:10.1074/jbc.M408238200

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Papers In Press, published online ahead of print October 13, 2004
J. Biol. Chem, 10.1074/jbc.M408238200
Submitted on July 21, 2004
Revised on September 27, 2004
Accepted on October 13, 2004

NF-KappaB family proteins participates in multiple steps of hematopoiesis through elimination of reactive oxygen species

Soichi Nakata, Itaru Matsumura, Hirokazu Tanaka, Sachiko Ezoe, Yusuke Satoh, Jun Ishikawa, Takumi Era, and Yuzuru Kanakura

Department of Hematology and Oncology, Osaka University, Suita, Osaka 565-0879

Corresponding Author: matumura{at}bldon.med.osaka-u.ac.jp

To examine the roles for NF- $kappa$ B family proteins in hematopoiesis, we first expressed dominant negative Rel/NF- $kappa$ B (I $kappa$ BSR) in a factor-dependent cell line, Ba/F3. Although I $kappa$ BSR neither affected TPO-dependent nor gp130-mediated growth, it suppressed IL-3- and EPO-dependent growth at low concentrations. In addition, I $kappa$ BSR enhanced factor-deprived apoptosis through the accumulation of reactive oxygen species (ROS). When expressed in normal hematopoietic stem/progenitor cells, I $kappa$ BSR induced apoptosis even in the presence of appropriate cytokines by accumulating ROS. We also expressed I $kappa$ BSR in an inducible fashion at various stages of hematopoiesis using the OP9 system, in which hematopoietic cells are induced to develop from ES cells. When I $kappa$ BSR was expressed at the stage of Flk-1+ cells (putative hemangioblasts), I $kappa$ BSR inhibited the development of primitive hematopoietic progenitor cells by inducing apoptosis through the ROS accumulation. Furthermore, when I $kappa$ BSR was expressed after the development of hematopoietic progenitor cells, it inhibited their terminal differentiation towards erythrocytes, megakaryocytes, and granulocytes by inducing apoptosis through the ROS accumulation. These results indicate that NF- $kappa$ B is required for preventing apoptosis at multiple steps of hematopoiesis by eliminating ROS.

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