Abstract
To examine the roles for NF-kappaB family proteins in hematopoiesis, we first expressed dominant negative Rel/NF-kappaB(IkappaBSR) in a factor-dependent cell line, Ba/F3. Although IkappaBSR neither affected thrombopoietin-dependent nor gp130-mediated growth, it suppressed interleukin-3- and erythropoietin-dependent growth at low concentrations. In addition, IkappaBSR enhanced factor-deprived apoptosis through the accumulation of reactive oxygen species (ROS). When expressed in normal hematopoietic stem/progenitor cells, IkappaBSR induced apoptosis even in the presence of appropriate cytokines by accumulating ROS. We also expressed IkappaBSR in an inducible fashion at various stages of hematopoiesis using the OP9 system, in which hematopoietic cells are induced to develop from embryonic stem cells. When IkappaBSR was expressed at the stage of Flk-1(+) cells (putative hemangioblasts), IkappaBSR inhibited the development of primitive hematopoietic progenitor cells by inducing apoptosis through the ROS accumulation. Furthermore, when IkappaBSR was expressed after the development of hematopoietic progenitor cells, it inhibited their terminal differentiation toward erythrocytes, megakaryocytes, and granulocytes by inducing apoptosis through the ROS accumulation. These results indicate that NF-kappaB is required for preventing apoptosis at multiple steps of hematopoiesis by eliminating ROS.
Highlights
To examine the roles for NF-B family proteins in hematopoiesis, we first expressed dominant negative Rel/NF-B (IBSR) in a factor-dependent cell line, Ba/F3
Recent studies have demonstrated that these factors are constitutively activated in various types of hematologic malignancies, including lymphomas (Hodgkin’s disease, adult T-cell leukemia/lymphoma, Burkitt’s lymphoma, and anaplastic lymphoma), multiple myeloma, acute myeloid leukemia, and acute lymphoblastic leukemia, thereby causing these diseases and/or affecting their pathophysiologic aspects [32]
These results suggest that the appropriate regulation of NF-B activity is required for normal hematopoiesis
Summary
To examine the roles for NF-B family proteins in hematopoiesis, we first expressed dominant negative Rel/NF-B (IBSR) in a factor-dependent cell line, Ba/F3. When expressed in normal hematopoietic stem/progenitor cells, IBSR induced apoptosis even in the presence of appropriate cytokines by accumulating ROS.
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