Phenotypes Associated with This Genotype

Genotype
MGI:8209199

• Allelic Composition: Gt(ROSA)26Sor^{tm1(CAG-SETBP1*G870S,-EGFP)Ase}/Gt(ROSA)26Sor⁺; Commd10^{Tg(Vav1-icre)A2Kio}/Commd10⁺
• Genetic Background: involves: C57BL/6N * C57BL/10 * CBA/Ca

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:363041 )

• median survival of 108 days

• 100% of mice succumb of multiorgan failure due to extreme leukocytosis

behavior/neurological

lethargy ( J:363041 )

• moribund mice appear lethargic

growth/size/body

hepatosplenomegaly ( J:363041 )

hematopoietic system

abnormal hematopoietic system morphology/development ( J:363041 )

• mice show signs of hematological disease between 30 and 90 days after birth, developing a myeloproliferative neoplasm (MPN) disease characterized by myelofibrosis, megakaryocytic-restricted dysplasia, marked mature leukocytosis, and progressive splenomegaly

increased common myeloid progenitor cell number ( J:363041 )

• bone marrow shows an expansion of common myeloid progenitors (CMPs)

extramedullary hematopoiesis ( J:363041 )

• clusters of variably segmented myeloid cells accumulate in the liver and in the red pulp of the spleen indicating extramedullary hematopoiesis

anemia ( J:363041 )

• anemia is exacerbated in lethally irradiated syngenic recipients receiving bone marrow cells from mutant doners and transplanted mice die within 16 days after transplant because of extreme anemia

• mild anemia is seen in sublethally irradiated syngenic recipients receiving bone marrow cells from mutant doners and all transplanted mice develop an accelerated form of chronic myeloproliferation

abnormal bone marrow cell number ( J:363041 )

• bone marrow shows an expansion of lineage-negative (Lin-) cells

abnormal megakaryocyte morphology ( J:363041 )

• atypical megakaryocytes are commonly seen in the bone marrow, with frequent hypolobulated bulbous nuclei, dark chromatin with irregular borders, and folding of the nuclear surface

thrombocytopenia ( J:363041 )

• peripheral blood shows lower platelet counts

• thrombocytopenia is exacerbated in lethally irradiated syngenic recipients receiving bone marrow cells from mutant doners

decreased lymphocyte cell number ( J:363041 )

increased leukocyte cell number ( J:363041 )

• 100% of mice succumb of multiorgan failure due to extreme leukocytosis

• massive leukocytosis is seen in sublethally irradiated syngenic recipients receiving bone marrow cells from mutant doners and all transplanted mice develop an accelerated form of chronic myeloproliferation

increased myeloid cell number ( J:363041 )

• peripheral blood shows an imbalance between the lymphoid and myeloid lineages in favor of the latter, with an increase of mature myeloid cells and a reduction in the percentage of lymphocytes

• -however, no evidence of granulocytic dysplasia is seen and no circulating blasts or nonsegmented myeloid precursors are seen in the peripheral blood

myeloid hyperplasia ( J:363041 )

• bone marrow shows overt myeloid hyperplasia with no evidence of dysplasia except for the megakaryotic lineage

decreased hematopoietic stem cell number ( J:363041 )

• within the Lin- population, the fraction of multipotent Lin-/Sca1+/c-Kit+ (LSK) cells is reduced and very few hematopoietic stem cells (HSCs; CD150+/CD48-) are seen

• however, no change in the MPP fraction (CD150-/CD48+) is seen

abnormal spleen morphology ( J:363041 )

• spleen shows distortion of the normal architecture

• spleen shows massive infiltration by mature myeloid cells and a loss of lymphoid cells

• spleen shows an aberrantly large Lin- population, with a significant fraction being c-Kit+/Sca1-, suggesting a myeloid progenitor phenotype

hepatosplenomegaly ( J:363041 )

immune system

myeloid hyperplasia ( J:363041 )

• bone marrow shows overt myeloid hyperplasia with no evidence of dysplasia except for the megakaryotic lineage

decreased lymphocyte cell number ( J:363041 )

increased leukocyte cell number ( J:363041 )

• 100% of mice succumb of multiorgan failure due to extreme leukocytosis

• massive leukocytosis is seen in sublethally irradiated syngenic recipients receiving bone marrow cells from mutant doners and all transplanted mice develop an accelerated form of chronic myeloproliferation

abnormal spleen morphology ( J:363041 )

• spleen shows distortion of the normal architecture

• spleen shows massive infiltration by mature myeloid cells and a loss of lymphoid cells

• spleen shows an aberrantly large Lin- population, with a significant fraction being c-Kit+/Sca1-, suggesting a myeloid progenitor phenotype

hepatosplenomegaly ( J:363041 )

liver/biliary system

abnormal liver morphology ( J:363041 )

• liver shows distortion of the normal architecture

hepatosplenomegaly ( J:363041 )

skeleton

myelofibrosis ( J:363041 )

• adult mice show stromal changes with reticulin fibrosis in the bone marrow

• bone marrow shows an increased network of reticulin fibers with many intersections, with a predominant peritrabecular distribution but also extending within the intertrabecular spaces, and the presence of thick, confluent collagen fibers

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
myelofibrosis		DOID:4971	OMIM:254450	J:363041