Phenotypes Associated with This Genotype

Genotype
MGI:4819157

• Allelic Composition: Zfp36l1^tm1.1Tnr/Zfp36l1^tm1.1Tnr; Zfp36l2^tm1.1Tnr/Zfp36l2^tm1.1Tnr; Tg(CD2-icre)4Kio/0
• Genetic Background: involves: C57BL/6 * C57BL/10 * CBA/Ca * SJL

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

mortality/aging

premature death ( J:162388 )

• by 6 months of age, 90% of the mutant mice die or are humanely killed because of their ill health

neoplasm

increased T cell derived lymphoma incidence ( J:162388 )

• all mutant mice develop thymic tumors

• thymic tumors have high CD8 expression, with variable CD4 expression

• high expression of heat-stable antigen (CD24) but do not have surface expression of the TCR beta-chain (TCRbeta)

• most but not all tumors have intracellular expression of TCRbeta

• Notch1 mutation is present in a minority of tumors and affected mainly the heterodimerization domain (25%) rather than the PEST domain (8%)

• primary tumor cells cultured in vitro are Notch1 dependent and killed by Zfp36l1 re-expression

increased leukemia incidence ( J:162388 )

• development of T cell acute lymphoblastic leukemia

• circulating lymphoblasts in peripheral blood

• tumor cells in thymus, spleen, lymph node and bone marrow

• predominantly oligoclonal

• corresponding to the CD8+ immature single-positive (CD8iSP) and double-positive (DP) stages of thymic development

immune system

abnormal thymus development ( J:162388 )

• perturbed thymopoiesis before tumor development

• thymic atrophy at 3 and 8 weeks of age

• gradual expansion of the CD8iSP population (CD8+CD4_CD24hi, membrane TCRbeta negative) in both proportion and absolute number by 13 weeks

• less progression from double-negative 2 (DN2) (CD44+CD25+) to DN3 (CD44_CD25+)

• decreased proportion of DN thymocytes with icTCRbeta expression

• only 30% of CD8iSP cells and 90% of DP cells have icTCRbeta expression

thymus atrophy ( J:162388 )

• thymic atrophy at 3 and 8 weeks of age

• total thymic cellularity is approximately 50% that of control mice

increased T cell derived lymphoma incidence ( J:162388 )

• all mutant mice develop thymic tumors

• thymic tumors have high CD8 expression, with variable CD4 expression

• high expression of heat-stable antigen (CD24) but do not have surface expression of the TCR beta-chain (TCRbeta)

• most but not all tumors have intracellular expression of TCRbeta

• Notch1 mutation is present in a minority of tumors and affected mainly the heterodimerization domain (25%) rather than the PEST domain (8%)

• primary tumor cells cultured in vitro are Notch1 dependent and killed by Zfp36l1 re-expression

enlarged spleen ( J:162388 )

• many mutant mice have splenomegaly

enlarged lymph nodes ( J:162388 )

• many mutant mice have lymphadenopathy

cellular

increased cell proliferation ( J:162388 )

• increased cellular proliferation by EdU staining in thymic populations from mice aged 5 and 10 weeks old

hematopoietic system

abnormal thymus development ( J:162388 )

• perturbed thymopoiesis before tumor development

• thymic atrophy at 3 and 8 weeks of age

• gradual expansion of the CD8iSP population (CD8+CD4_CD24hi, membrane TCRbeta negative) in both proportion and absolute number by 13 weeks

• less progression from double-negative 2 (DN2) (CD44+CD25+) to DN3 (CD44_CD25+)

• decreased proportion of DN thymocytes with icTCRbeta expression

• only 30% of CD8iSP cells and 90% of DP cells have icTCRbeta expression

thymus atrophy ( J:162388 )

• thymic atrophy at 3 and 8 weeks of age

• total thymic cellularity is approximately 50% that of control mice

increased T cell derived lymphoma incidence ( J:162388 )

• all mutant mice develop thymic tumors

• thymic tumors have high CD8 expression, with variable CD4 expression

• high expression of heat-stable antigen (CD24) but do not have surface expression of the TCR beta-chain (TCRbeta)

• most but not all tumors have intracellular expression of TCRbeta

• Notch1 mutation is present in a minority of tumors and affected mainly the heterodimerization domain (25%) rather than the PEST domain (8%)

• primary tumor cells cultured in vitro are Notch1 dependent and killed by Zfp36l1 re-expression

enlarged spleen ( J:162388 )

• many mutant mice have splenomegaly

endocrine/exocrine glands

abnormal thymus development ( J:162388 )

• perturbed thymopoiesis before tumor development

• thymic atrophy at 3 and 8 weeks of age

• gradual expansion of the CD8iSP population (CD8+CD4_CD24hi, membrane TCRbeta negative) in both proportion and absolute number by 13 weeks

• less progression from double-negative 2 (DN2) (CD44+CD25+) to DN3 (CD44_CD25+)

• decreased proportion of DN thymocytes with icTCRbeta expression

• only 30% of CD8iSP cells and 90% of DP cells have icTCRbeta expression

thymus atrophy ( J:162388 )

• thymic atrophy at 3 and 8 weeks of age

• total thymic cellularity is approximately 50% that of control mice

increased T cell derived lymphoma incidence ( J:162388 )

• all mutant mice develop thymic tumors

• thymic tumors have high CD8 expression, with variable CD4 expression

• high expression of heat-stable antigen (CD24) but do not have surface expression of the TCR beta-chain (TCRbeta)

• most but not all tumors have intracellular expression of TCRbeta

• Notch1 mutation is present in a minority of tumors and affected mainly the heterodimerization domain (25%) rather than the PEST domain (8%)

• primary tumor cells cultured in vitro are Notch1 dependent and killed by Zfp36l1 re-expression

growth/size/body

enlarged spleen ( J:162388 )

• many mutant mice have splenomegaly

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
acute lymphoblastic leukemia		DOID:9952	OMIM:247640 OMIM:613065	J:162388