Figure 7
Figure 7. PRDX2 inhibits leukemogenesis in Myc-associated BM transplantation model. (A) Primary murine BM was retrovirally transduced with either c-myc alone or with simultaneous PRDX2 expression (PRDX2–c-myc). Similar numbers of transduced BM cells (indicated by GFP expression) were transplanted into lethally radiated recipients. Leukemia development and survival were followed over time. The Kaplan-Meier plots indicate a significantly prolonged latency and less penetrance on PRDX2 expression (P = .008, log-rank test). (B) Weight distribution of spleens of the mice that received a transplant at the time of leukemia development (for PRDX2-Myc animals, > 10 weeks after transplantation). Data shown here are from 10 individual mice analyzed for each group. Significance was calculated by nonparametric Mann-Whitney U test. (C) Photographic image of spleens of the mice that received a transplant (1 representative mouse from each group) at the time of disease development. (D) Immunophenotype of BM cells obtained from mice that received a transplant with c-Myc or Prdx2–c-Myc analyzed by flow cytometry. BM cells were stained for surface expression of indicated markers, and cells were acquired with BD FACSCalibur, and data were analyzed with CellQuest Version 6.0 software (BD Biosciences). (E) Cytospin structure from mice that received a transplant with c-Myc or Prdx2-c-Myc–transduced BM. Cytospin preparations of BM cells were stained with Wright-Giemsa (original magnification, ×60). Pictures were taken on an Axio Imager M1 (Carl Zeiss Imaging Systems) with a 63×/1.4 oil objective at room temperature and processed by AxioVision Release 4.5 (Carl Zeiss Imaging Systems). (F) Model of the role of ROS and PRDX2 silencing in leukemogenesis. ROS is induced by various mechanisms in leukemogenesis, including cytokine signaling or c-Myc overexpression. Increased ROS levels enhance signaling and lead to increased expression of proliferation and cell survival genes. In addition, ROS levels induce genomic instability. ROS molecules are scavenged by PRDX2, which leads to decreases in signaling and potentially also genomic instability. The frequent epigenetic silencing of PRDX2 in AML can lead to increase in ROS levels and thereby enhanced signaling and proliferative capacity of leukemia cells.

PRDX2 inhibits leukemogenesis in Myc-associated BM transplantation model. (A) Primary murine BM was retrovirally transduced with either c-myc alone or with simultaneous PRDX2 expression (PRDX2–c-myc). Similar numbers of transduced BM cells (indicated by GFP expression) were transplanted into lethally radiated recipients. Leukemia development and survival were followed over time. The Kaplan-Meier plots indicate a significantly prolonged latency and less penetrance on PRDX2 expression (P = .008, log-rank test). (B) Weight distribution of spleens of the mice that received a transplant at the time of leukemia development (for PRDX2-Myc animals, > 10 weeks after transplantation). Data shown here are from 10 individual mice analyzed for each group. Significance was calculated by nonparametric Mann-Whitney U test. (C) Photographic image of spleens of the mice that received a transplant (1 representative mouse from each group) at the time of disease development. (D) Immunophenotype of BM cells obtained from mice that received a transplant with c-Myc or Prdx2–c-Myc analyzed by flow cytometry. BM cells were stained for surface expression of indicated markers, and cells were acquired with BD FACSCalibur, and data were analyzed with CellQuest Version 6.0 software (BD Biosciences). (E) Cytospin structure from mice that received a transplant with c-Myc or Prdx2-c-Myc–transduced BM. Cytospin preparations of BM cells were stained with Wright-Giemsa (original magnification, ×60). Pictures were taken on an Axio Imager M1 (Carl Zeiss Imaging Systems) with a 63×/1.4 oil objective at room temperature and processed by AxioVision Release 4.5 (Carl Zeiss Imaging Systems). (F) Model of the role of ROS and PRDX2 silencing in leukemogenesis. ROS is induced by various mechanisms in leukemogenesis, including cytokine signaling or c-Myc overexpression. Increased ROS levels enhance signaling and lead to increased expression of proliferation and cell survival genes. In addition, ROS levels induce genomic instability. ROS molecules are scavenged by PRDX2, which leads to decreases in signaling and potentially also genomic instability. The frequent epigenetic silencing of PRDX2 in AML can lead to increase in ROS levels and thereby enhanced signaling and proliferative capacity of leukemia cells.

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