Page 58 - 2014 Printable Abstract Book
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exclusively develop in the small intestine and increased intestinal tumor frequency was radiation quality
dependent, we investigated persistent effects of radiation quality on ISC as well as on differentiated
intestinal epithelial cells in mice. Mice (6 to 8 week; C57BL/6J) were exposed to γ (0.5 and 2 Gy) and 56Fe
(0.5 and 1.6 Gy) radiation, samples were collected 7 d and 2 m after radiation exposure, and carcinogenic
precursor events such as persistent oxidative stress and DNA damage were assessed. Higher persistently
increased oxidative stress and oxidative DNA damage was observed after 56Fe relative to γ radiation.
However, increased oxidative stress did not increase cell death implying that the oxidative stress was sub-
lethal. Autophagy, a self-cannibalistic process of cell involved in removing damaged cell and cell
constituents, was consistently inhibited in a radiation quality dependent manner even 2 m after exposure
suggesting persistence of damage-bearing cells. We believe radiation-induced autophagy inhibition and
sub-lethal oxidative stress is working in tandem to trigger proliferative signaling such as PI3K/Akt and
mTOR in intestinal cells. Taken together our results provide insight into radiation quality dependent
persistent cancer-related molecular events, which could have altered phenotypic behavior of ISC such as
proliferation, differentiation, and migration.
(S1202) The Response of Hematopoietic Stem/Progenitor Cells to Radiation Regulates
Lymphomagenesis. Chang-Lung Lee; David G. Kirsch, Duke University Medical Center, Durham, NC
Hematopoietic cells are sensitive to radiation. Accidental or deliberate exposure to ionizing
radiation can cause acute hematopoietic toxicity, a long-term decrease in competiveness of
hematopoietic stem/progenitor cells (HSPCs), and an increased risk of leukemia and lymphoma. Using a
mouse model of radiation-induced thymic lymphoma, Kaplan and colleagues performed a series of
transplant experiments to demonstrate that radiation-induced lymphoma in the thymus can be
suppressed by transplanting non-irradiated, but not irradiated, bone marrow cells. These studies
indicated that radiation-induced lymphomagenesis is associated with defects in thymic engraftment of
bone marrow-derived HSPCs. However, a mechanistic link between radiation-induced lymphomagenesis
in the thymus and decreased competiveness of irradiated HSPCs has remained elusive for decades. One
key gene that regulates radiosensitivity of HSPCs is the tumor suppressor p53. We have utilized transgenic
mice expressing an inducible shRNA against p53 to discover that temporary knockdown of p53 during
total-body irradiation (TBI) significantly improved short-term hematopoietic reconstitution and increased
long-term engraftment of HSPCs. Remarkably, temporary knockdown of p53 during TBI also significantly
reduced the incidence of thymic lymphoma. In addition, experiments with “Super p53” mice, which harbor
an extra copy of p53, show that an enhanced p53 response to TBI exacerbated the hematopoietic acute
radiation syndrome and failed to suppress radiation-induced lymphoma formation. Together, our results
demonstrate that the acute p53 response to TBI decreases fitness of HSPCs and promotes the formation
of radiation-induced thymic lymphoma. Our studies support a model in which p53 acts during total-body
irradiation to promote lymphomagenesis and provides a molecular mechanism to explain the observation
that radiation carcinogenesis can develop in non-targeted tissues.
56 | P a g e
dependent, we investigated persistent effects of radiation quality on ISC as well as on differentiated
intestinal epithelial cells in mice. Mice (6 to 8 week; C57BL/6J) were exposed to γ (0.5 and 2 Gy) and 56Fe
(0.5 and 1.6 Gy) radiation, samples were collected 7 d and 2 m after radiation exposure, and carcinogenic
precursor events such as persistent oxidative stress and DNA damage were assessed. Higher persistently
increased oxidative stress and oxidative DNA damage was observed after 56Fe relative to γ radiation.
However, increased oxidative stress did not increase cell death implying that the oxidative stress was sub-
lethal. Autophagy, a self-cannibalistic process of cell involved in removing damaged cell and cell
constituents, was consistently inhibited in a radiation quality dependent manner even 2 m after exposure
suggesting persistence of damage-bearing cells. We believe radiation-induced autophagy inhibition and
sub-lethal oxidative stress is working in tandem to trigger proliferative signaling such as PI3K/Akt and
mTOR in intestinal cells. Taken together our results provide insight into radiation quality dependent
persistent cancer-related molecular events, which could have altered phenotypic behavior of ISC such as
proliferation, differentiation, and migration.
(S1202) The Response of Hematopoietic Stem/Progenitor Cells to Radiation Regulates
Lymphomagenesis. Chang-Lung Lee; David G. Kirsch, Duke University Medical Center, Durham, NC
Hematopoietic cells are sensitive to radiation. Accidental or deliberate exposure to ionizing
radiation can cause acute hematopoietic toxicity, a long-term decrease in competiveness of
hematopoietic stem/progenitor cells (HSPCs), and an increased risk of leukemia and lymphoma. Using a
mouse model of radiation-induced thymic lymphoma, Kaplan and colleagues performed a series of
transplant experiments to demonstrate that radiation-induced lymphoma in the thymus can be
suppressed by transplanting non-irradiated, but not irradiated, bone marrow cells. These studies
indicated that radiation-induced lymphomagenesis is associated with defects in thymic engraftment of
bone marrow-derived HSPCs. However, a mechanistic link between radiation-induced lymphomagenesis
in the thymus and decreased competiveness of irradiated HSPCs has remained elusive for decades. One
key gene that regulates radiosensitivity of HSPCs is the tumor suppressor p53. We have utilized transgenic
mice expressing an inducible shRNA against p53 to discover that temporary knockdown of p53 during
total-body irradiation (TBI) significantly improved short-term hematopoietic reconstitution and increased
long-term engraftment of HSPCs. Remarkably, temporary knockdown of p53 during TBI also significantly
reduced the incidence of thymic lymphoma. In addition, experiments with “Super p53” mice, which harbor
an extra copy of p53, show that an enhanced p53 response to TBI exacerbated the hematopoietic acute
radiation syndrome and failed to suppress radiation-induced lymphoma formation. Together, our results
demonstrate that the acute p53 response to TBI decreases fitness of HSPCs and promotes the formation
of radiation-induced thymic lymphoma. Our studies support a model in which p53 acts during total-body
irradiation to promote lymphomagenesis and provides a molecular mechanism to explain the observation
that radiation carcinogenesis can develop in non-targeted tissues.
56 | P a g e
