Analysis Tools
mortality/aging
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• homozygotes exhibit a significantly shortened lifespan as a result of hemolytic anemia and malignant tumors
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endocrine/exocrine glands
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• 3% of homozygotes develop breast adenocarcinomas
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• 9% of homozygotes develop pancreatic islet cell adenomas
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hematopoietic system
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• massive splenomegaly is sometimes observed due to extensive extramedullary hematopoiesis
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• a subset of homozygotes develop fatal hemolytic anemia as they age; this anemia is attributed to a reduction in intrinsic erythrocyte survival, as biotin-labeled erythrocytes from anemic mutants have half-lives of 10 days after adoptive transfer to wild-type recipients versus 25 days for wild-type erythrocytes
• hemolytic anemia is first evident at 9 months of age, and is typified by an increase in erythrocyte reactive oxygen species (ROS) leading to protein oxidation, hemoglobin instability, Heinz body formation, and reduced erythrocyte lifespan
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• severely anemic homozygotes display abnormal erythrocyte morphology
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• many premorbid homozygotes are severely anemic with significantly reduced hematocrits
• however, leukocyte and platelet counts remain unaffected
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• severely anemic homozygotes display an increase in the width of erythrocyte volume distribution
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• many premorbid homozygotes show a significantly reduced level of hemoglobin in peripheral blood
• many ageing homozygotes display precipitous drops in blood hemoglobin over a period of 1-2 months, coincident with and in some cases preceded by a rise in circulating reticulocytes
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anisocytosis
(
J:84677
)
microcytosis
(
J:84677
)
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• homozygotes exhibit a 40%-90% increase in the frequency of splenic CD3-NK1.1+ cells as well as a 2- to 3-fold increase in the frequency of NK1.1+Ly49A+ cells relative to wild-type mice
• in contrast, the frequency of NK1.1+Ly49D+ is reduced to <80% of wild-type values
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• anemic homozygotes show a 10-fold increase in the number of peripheral reticulocytes relative to wild-type controls
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• spleens from anemic homozygotes exhibit a disrupted follicular architecture as a result of extramedullary hematopoiesis
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• anemic homozygotes frequently display splenomegaly at autopsy
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• anemic homozygotes show a 5-fold increase in spleen weight relative to wild-type controls
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• partially purified splenic NK cells from mutant mice exhibit a significant reduction in lytic activity towards YAC-1 target cells
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growth/size/body
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• anemic homozygotes frequently display splenomegaly at autopsy
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• anemic homozygotes show a 5-fold increase in spleen weight relative to wild-type controls
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neoplasm
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• 50% of homozygotes succumbed to malignancy either alone or in combination with hemolytic anemia
• 38% of tumour-bearing homozygotes had two independent malignancies, while 6% of homozygotes were diagnosed with three different tumours
• in addition to B and T lymphomas and histiocytic malignancy (also observed in aging wild-type controls), malignancies found in homozygous mutant mice included epithelial and mesenchymal tumours (hepatocellular carcinoma, fibrosarcoma, osteosarcoma, islet cell adenomas, and adenocarcinomas of lung and breast), which are less common in aging control mice
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• 9% of homozygotes develop pancreatic islet cell adenomas
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• 21% of homozygotes develop lymphomas
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• 44% of homozygotes develop histiocytic sarcomas
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• 3% of homozygotes develop breast adenocarcinomas
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• 34% of homozygotes develop hepatocellular carcinomas
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• 3% of homozygotes develop lung adenocarcinomas
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• 9% of homozygotes develop fibrosarcomas
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• 16% of homozygotes develop hemangiosarcomas
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integument
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• 3% of homozygotes develop breast adenocarcinomas
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liver/biliary system
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• 34% of homozygotes develop hepatocellular carcinomas
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cellular
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• mutant MEFs exhibit a higher fraction of cells in the G1 phase of the cell cycle (61%) than wild-type MEFs (44%)
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• mutant MEFs proliferate more slowly than wild-type MEFs
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• erythrocytes from anemic homozygotes display an increase in baseline ROS
• mutant MEFs exhibit significantly lower clonogenic survival in response to oxidant treatment
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• erythrocytes from anemic homozygotes display an increase in ROS generated in response to hydrogen peroxide challenge
• mutant MEFs display higher concentrations of peroxide-induced cellular ROS relative to wild-type MEFs
• in addition, mutant MEFs show significantly higher basal and peroxide-induced concentrations of 8-oxoguanine than wild-type MEFs; staining is mostly nuclear and is significantly blocked by preincubating avidin-FITC with an 8-oxoG-containing oligonucleotide but not a non-oxidized oligonucleotide
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immune system
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• homozygotes exhibit a 40%-90% increase in the frequency of splenic CD3-NK1.1+ cells as well as a 2- to 3-fold increase in the frequency of NK1.1+Ly49A+ cells relative to wild-type mice
• in contrast, the frequency of NK1.1+Ly49D+ is reduced to <80% of wild-type values
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• spleens from anemic homozygotes exhibit a disrupted follicular architecture as a result of extramedullary hematopoiesis
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• anemic homozygotes frequently display splenomegaly at autopsy
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• anemic homozygotes show a 5-fold increase in spleen weight relative to wild-type controls
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• partially purified splenic NK cells from mutant mice exhibit a significant reduction in lytic activity towards YAC-1 target cells
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respiratory system
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• 3% of homozygotes develop lung adenocarcinomas
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homeostasis/metabolism
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• erythrocytes from anemic homozygotes display an increase in baseline ROS
• mutant MEFs exhibit significantly lower clonogenic survival in response to oxidant treatment
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• erythrocytes from anemic homozygotes display an increase in ROS generated in response to hydrogen peroxide challenge
• mutant MEFs display higher concentrations of peroxide-induced cellular ROS relative to wild-type MEFs
• in addition, mutant MEFs show significantly higher basal and peroxide-induced concentrations of 8-oxoguanine than wild-type MEFs; staining is mostly nuclear and is significantly blocked by preincubating avidin-FITC with an 8-oxoG-containing oligonucleotide but not a non-oxidized oligonucleotide
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• anemic homozygotes display increased blood lactate dehydrogenase and reduced haptoglobin, indicating intravascular destruction of erythrocytes
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• anemic homozygotes display increased blood lactate dehydrogenase and reduced haptoglobin, indicating intravascular destruction of erythrocytes
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