Analysis Tools
mortality/aging
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• mice exhibit premature death, with an average lifespan of 675 days versus 823 days in wild-type controls
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growth/size/body
weight loss
(
J:233169
)
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• mice exhibit progressive weight loss starting from 6 months of age
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• mice suffer an extended period of illness, starting from 6 months to 1 year of age characterized by progressive weight loss and wasting
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• marked splenomegaly upon necropsy, resulting from extramedullary hematopoiesis and expansion of the myeloid lineage
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• mean spleen weight is significantly increased from 8 to 20 months of age
• treatment with IGF1R kinase inhibitor NVP-AEW541 for 2 months restores spleen weight to wild-type levels
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hematopoietic system
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• marked splenomegaly upon necropsy, resulting from extramedullary hematopoiesis and expansion of the myeloid lineage
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• mean spleen weight is significantly increased from 8 to 20 months of age
• treatment with IGF1R kinase inhibitor NVP-AEW541 for 2 months restores spleen weight to wild-type levels
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• alterations in central hematopoiesis
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• increased total and common myeloid progenitor (CMP) cell number in the spleen at 6 months of age
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• bone marrow displays a marked reduction in cell number and trilineage dysplasia at later stages
• reduction in the % and absolute numbers of LSK+CD48-CD150+ cells (SLAMs) in the bone marrow at 6 months of age
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• bone marrow displays hypercellularity and trilineage hyperplasia at initial stages
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• increased total progenitor cell number and granulocyte-monocyte progenitor (GMP) cell number in the bone marrow at 6 months of age
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• decreased lymphocyte number in spleen but not in bone marrow at 6 months of age
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• elevated total leukocyte number in peripheral blood at 1.5 and 18 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 1 or 2 months leads to a significant reduction in peripheral leukocyte number
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• elevated lymphocyte number in peripheral blood at 1.5 and 18 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 1 or 2 months leads to a significant reduction in peripheral lymphocyte number
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• reduction in the % and absolute numbers of LSK+CD48-CD150+ cells (SLAM-enriched long-term HSCs) in the bone marrow and spleen at 6 months of age
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• increased % and absolute number of primitive Lin-SCA-1+c-KIT+ (LSK+) cells in the bone marrow and spleen at 6 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 2 months restores % and absolute number of LSK+ cells in the bone marrow and spleen to wild-type levels
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• progressive myeloid skewing with a left-shifted myeloid maturation pattern
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• decreased number of mature myeloid cells in the bone marrow at 6 months of age
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• increased granulocyte-monocyte progenitor (GMP) cell number in the bone marrow and spleen at 6 months of age
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• increased hematocrit at 1.5 and 18 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 1 or 2 months leads to a significant hematocrit reduction
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• increased number of nucleated red cells in the bone marrow but not in spleen at 6 months of age
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• splenomegaly due to expansion of the myeloid lineage
• increased immature and mature myeloid cells in spleen at 6 months of age
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• increased platelet number at 1.5 and 18 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 1 or 2 months leads to a significant reduction in platelet number
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• increased megakaryocyte-erythrocyte progenitor (MEP) cell number in the spleen at 6 months of age
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• high percentage of bands, metamyelocyte and blast cell populations in white blood cells at 18 months of age
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• elevated granulocyte number in peripheral blood at 1.5 and 18 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 1 or 2 months leads to a significant reduction in peripheral granulocyte number
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• competitive disadvantage over wild-type cells in repopulation assays
• primary HSC defect as revealed by reciprocal bone marrow transplantation experiments
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neoplasm
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• mice develop a fully-penetrant myeloproliferative neoplastic (MPN) process
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 2 months reverses MPN-related hematologic alterations
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skeleton
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• bone marrow displays myelofibrosis at later stages
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homeostasis/metabolism
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• >10-fold increase in total IGF1R (insulin-like growth factor I receptor) protein levels in the bone marrow resulting in a 3.6-fold increase in IGF1R phosphorylation and activation of its targets
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immune system
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• marked splenomegaly upon necropsy, resulting from extramedullary hematopoiesis and expansion of the myeloid lineage
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• mean spleen weight is significantly increased from 8 to 20 months of age
• treatment with IGF1R kinase inhibitor NVP-AEW541 for 2 months restores spleen weight to wild-type levels
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• decreased lymphocyte number in spleen but not in bone marrow at 6 months of age
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• elevated total leukocyte number in peripheral blood at 1.5 and 18 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 1 or 2 months leads to a significant reduction in peripheral leukocyte number
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• elevated lymphocyte number in peripheral blood at 1.5 and 18 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 1 or 2 months leads to a significant reduction in peripheral lymphocyte number
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• high percentage of bands, metamyelocyte and blast cell populations in white blood cells at 18 months of age
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• elevated granulocyte number in peripheral blood at 1.5 and 18 months of age
• daily treatment with IGF1R kinase inhibitor NVP-AEW541 for 1 or 2 months leads to a significant reduction in peripheral granulocyte number
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