Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Heterozygote x +/+ sibling         (Female x Male)   15-OCT-10 Species laboratory mouse Generation N10+N1F0 (29-MAR-11) Generation Definitions   Donating Investigator D. Gary Gilliland,   Brigham and Women's Hospital

Description
These mice carry the human W51 mutation, ITD, internal tandem duplication of amino acids 596 to 602, in the endogenous mouse Flt3 locus, which confers constitutive FLT3 signaling. Mice that are homozygous for the targeted mutation are viable and fertile. The Donating Investigator reports that BALB/c mice carrying this allele are not as viable as mutants on the C57BL/6 background. Although FLT protein levels are comparable to wildtype, increased phospho-Flt3 (p-FLT3) and phospho-Stat5 (pSTAT5) levels are detected by flow cytometric analysis of homozygous bone marrow and splenic cells. Homozygotes exhibit leukocytosis, monocytosis and progressive splenomegaly. Mature myeloid and monocytic populations in homozygotes are increased, with reduced B and T cell populations. B cell development is arrested at the pre-B stage. Heterozygotes have decreased liver size, hemoglobin levels, platelet counts and exhibit a milder maturing myeloid hyperplasia phenotype when compared to homozygotes.

Development
The human W51 mutation (ITD, internal tandem duplication of amino acids 596 to 602) was inserted in-frame into exon 14 and a floxed neo cassette inserted downstream of exon 15. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl⁺ derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The donating investigator stated that the resulting chimeric animals were crossed to C57BL/6 mice, and then backcrossed to the same for 9 generations (see SNP note below). Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J at least once to establish the colony.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, all 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a C57BL/6N genetic background.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Myelocytic Leukemia-Like Syndrome, Familial, Chronic

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Leukemia, Acute Myeloid; AML   (FLT3)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Flt3^tm1Dgg/Flt3⁺

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• hematopoietic system phenotype
• abnormal hematopoiesis
  • bone marrow cells exhibit a two-fold increase in the Lin-Sca1+cKit+ (LSK) compartment compared to in wild-type mice   (MGI Ref ID J:126003)
  • fewer LSK cells undergo apoptosis compared to in wild-type   (MGI Ref ID J:126003)
  • monocytes are present in the bone marrow and liver in a background of increased number of maturing myeloid cells is increased compared to in wild-type mice   (MGI Ref ID J:126003)
• • abnormal B cell differentiation
    • B cell maturation is blocked at the pre-B stage   (MGI Ref ID J:126003)
  • decreased B cell number
    • the rise in monocytes in the bone marrow and spleen is accompanied by a decrease in the percentage of T and B lymphoid cells   (MGI Ref ID J:126003)
  • • decreased mature B cell number
      • the number of mature B cells in the bone marrow and spleen is decreased compared to in wild-type mice   (MGI Ref ID J:126003)
  • decreased T cell number
    • the rise in monocytes in the bone marrow and spleen is accompanied by a decrease in the percentage of T and B lymphoid cells   (MGI Ref ID J:126003)
  • increased leukocyte cell number
    • mice exhibit leukocytosis and monocytosis with a reversal in the neutrophil to lymphocyte ratio compared to in wild-type mice   (MGI Ref ID J:126003)
  • • increased granulocyte number
      • granulocyte populations are increased in peripheral blood compared to in wild-type mice   (MGI Ref ID J:126003)
    • increased monocyte cell number
      • monocyte populations are increased in peripheral blood   (MGI Ref ID J:126003)
      • monocytes are present in the bone marrow and liver in a background of increased number of maturing myeloid cells is increased compared to in wild-type mice   (MGI Ref ID J:126003)
• enlarged spleen
  • mice develop a variable and progressive splenomegaly that is not as severe as in homozygous mice   (MGI Ref ID J:126003)
• increased spleen red pulp amount
  • expanded red pulp is comprised of mainly mature myeloid and ad-mixed erythroid elements   (MGI Ref ID J:126003)
• increased spleen white pulp amount
  • expanded white pulp is comprised of cells resembling maturing monocytes   (MGI Ref ID J:126003)
• immune system phenotype
• abnormal B cell differentiation
  • B cell maturation is blocked at the pre-B stage   (MGI Ref ID J:126003)
• decreased B cell number
  • the rise in monocytes in the bone marrow and spleen is accompanied by a decrease in the percentage of T and B lymphoid cells   (MGI Ref ID J:126003)
• • decreased mature B cell number
    • the number of mature B cells in the bone marrow and spleen is decreased compared to in wild-type mice   (MGI Ref ID J:126003)
• decreased T cell number
  • the rise in monocytes in the bone marrow and spleen is accompanied by a decrease in the percentage of T and B lymphoid cells   (MGI Ref ID J:126003)
• enlarged spleen
  • mice develop a variable and progressive splenomegaly that is not as severe as in homozygous mice   (MGI Ref ID J:126003)
• increased leukocyte cell number
  • mice exhibit leukocytosis and monocytosis with a reversal in the neutrophil to lymphocyte ratio compared to in wild-type mice   (MGI Ref ID J:126003)
• • increased granulocyte number
    • granulocyte populations are increased in peripheral blood compared to in wild-type mice   (MGI Ref ID J:126003)
  • increased monocyte cell number
    • monocyte populations are increased in peripheral blood   (MGI Ref ID J:126003)
    • monocytes are present in the bone marrow and liver in a background of increased number of maturing myeloid cells is increased compared to in wild-type mice   (MGI Ref ID J:126003)
• increased spleen red pulp amount
  • expanded red pulp is comprised of mainly mature myeloid and ad-mixed erythroid elements   (MGI Ref ID J:126003)
• increased spleen white pulp amount
  • expanded white pulp is comprised of cells resembling maturing monocytes   (MGI Ref ID J:126003)
• cellular phenotype
• abnormal B cell differentiation
  • B cell maturation is blocked at the pre-B stage   (MGI Ref ID J:126003)

Flt3^tm1Dgg/Flt3^tm1Dgg

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• hematopoietic system phenotype
• abnormal hematopoiesis
  • bone marrow cells exhibit a two-fold increase in the Lin-Sca1+cKit+ (LSK) compartment compared to in wild-type and heterozygous mice   (MGI Ref ID J:126003)
  • monocytes are present in the bone marrow and liver in a background of increased number of maturing myeloid cells is increased compared to in wild-type mice   (MGI Ref ID J:126003)
  • the relative percentage of immunophenotypic granulocyte-monocyte progenitors is expanded while the percent of megakaryocyte-erythroid progenitors is decreased   (MGI Ref ID J:126003)
  • however, the total number of myeloid progenitor cells is the same as in wild-type mice   (MGI Ref ID J:126003)
  • the proportion of LSK cells in S/G2/M phase is increased while the proportion in G0/G1 is increased compared to in wild-type mice   (MGI Ref ID J:126003)
  • fewer LSK cells undergo apoptosis compared to in wild-type and heterozygous mice   (MGI Ref ID J:126003)
• • abnormal B cell differentiation
    • B cell maturation is blocked at the pre-B stage   (MGI Ref ID J:126003)
  • abnormal common myeloid progenitor cell morphology
    • when cultured on methylcellulose, bone marrow cells produce more colonies than wild-type cells with a greater number of monocytes and fewer erythroid burst forming units and granulocyte-erythroid burst forming units compared to wild-type and heterozygous mice   (MGI Ref ID J:126003)
    • however, re-plated colonies do not exhibit increased self-renewal properties   (MGI Ref ID J:126003)
  • decreased B cell number
    • the rise in monocytes in the bone marrow and spleen is accompanied by a decrease in the percentage of T and B lymphoid cells   (MGI Ref ID J:126003)
  • • decreased mature B cell number
      • the number of mature B cells in the bone marrow and spleen is decreased compared to in wild-type mice   (MGI Ref ID J:126003)
  • decreased T cell number
    • the rise in monocytes in the bone marrow and spleen is accompanied by a decrease in the percentage of T and B lymphoid cells   (MGI Ref ID J:126003)
  • increased leukocyte cell number
    • mice exhibit leukocytosis and monocytosis with a reversal in the neutrophil to lymphocyte ratio compared to in wild-type mice   (MGI Ref ID J:126003)
  • • increased granulocyte number
      • granulocyte populations are increased in peripheral blood compared to in wild-type mice   (MGI Ref ID J:126003)
    • increased monocyte cell number
      • monocyte populations are increased in peripheral blood   (MGI Ref ID J:126003)
      • monocytes are present in the bone marrow and liver in a background of increased number of maturing myeloid cells is increased compared to in wild-type mice   (MGI Ref ID J:126003)
• enlarged spleen
  • mice develop a variable and progressive splenomegaly that is more severe than in heterozygous mice   (MGI Ref ID J:126003)
• increased spleen red pulp amount
  • expanded red pulp is comprised of mainly mature myeloid and ad-mixed erythroid elements   (MGI Ref ID J:126003)
• increased spleen white pulp amount
  • expanded white pulp is comprised of cells resembling maturing monocytes   (MGI Ref ID J:126003)
• immune system phenotype
• abnormal B cell differentiation
  • B cell maturation is blocked at the pre-B stage   (MGI Ref ID J:126003)
• decreased B cell number
  • the rise in monocytes in the bone marrow and spleen is accompanied by a decrease in the percentage of T and B lymphoid cells   (MGI Ref ID J:126003)
• • decreased mature B cell number
    • the number of mature B cells in the bone marrow and spleen is decreased compared to in wild-type mice   (MGI Ref ID J:126003)
• decreased T cell number
  • the rise in monocytes in the bone marrow and spleen is accompanied by a decrease in the percentage of T and B lymphoid cells   (MGI Ref ID J:126003)
• enlarged spleen
  • mice develop a variable and progressive splenomegaly that is more severe than in heterozygous mice   (MGI Ref ID J:126003)
• increased leukocyte cell number
  • mice exhibit leukocytosis and monocytosis with a reversal in the neutrophil to lymphocyte ratio compared to in wild-type mice   (MGI Ref ID J:126003)
• • increased granulocyte number
    • granulocyte populations are increased in peripheral blood compared to in wild-type mice   (MGI Ref ID J:126003)
  • increased monocyte cell number
    • monocyte populations are increased in peripheral blood   (MGI Ref ID J:126003)
    • monocytes are present in the bone marrow and liver in a background of increased number of maturing myeloid cells is increased compared to in wild-type mice   (MGI Ref ID J:126003)
• increased spleen red pulp amount
  • expanded red pulp is comprised of mainly mature myeloid and ad-mixed erythroid elements   (MGI Ref ID J:126003)
• increased spleen white pulp amount
  • expanded white pulp is comprised of cells resembling maturing monocytes   (MGI Ref ID J:126003)
• cellular phenotype
• abnormal B cell differentiation
  • B cell maturation is blocked at the pre-B stage   (MGI Ref ID J:126003)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Flt3^tm1Dgg/Flt3⁺

        involves: 129S1/Sv * 129X1/SvJ * BALB/c

• hematopoietic system phenotype
• abnormal hematopoietic system morphology/development
  • authors state that mice display the same phenotype as when they are on a background containing C57BL/6   (MGI Ref ID J:126003)

Flt3^tm1Dgg/Flt3^tm1Dgg

        involves: 129S1/Sv * 129X1/SvJ * BALB/c

• hematopoietic system phenotype
• abnormal hematopoietic system morphology/development
  • authors state that mice display the same phenotype as when they are on a background containing C57BL/6   (MGI Ref ID J:126003)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cancer Research
Chronic Myelogenous Leukemia

Immunology, Inflammation and Autoimmunity Research
Lymphoid Tissue Defects
      myeloid hyperplasia

Research Tools
Cancer Research
      B cell deficiency
      Leukemia
Immunology and Inflammation Research
      B cell deficiency

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Flt3tm1Dgg
Allele Name		targeted mutation 1, D Gilliland
Allele Type		Targeted (knock-in)
Common Name(s)		FLT3/ITD; Flt3ITD;
Mutation Made By		D. Gary Gilliland,   Brigham and Women's Hospital
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Promoter		Flt3, FMS-like tyrosine kinase 3, mouse, laboratory
Molecular Note		The human W51 mutation which causes the duplication of amino acid 596 to 602 (R-E-Y-E-Y-D-L) was inserted inframe into exon 14. A floxed neomycin selection cassette was inserted in intron 15 as well. DNA sequencing was performed to confirm the duplication in exon 14. [MGI Ref ID J:126003]

Genotyping

Genotyping Information

Genotyping Protocols

Flt3^tm1Dgg, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Lee BH; Tothova Z; Levine RL; Anderson K; Buza-Vidas N; Cullen DE; McDowell EP; Adelsperger J; Frohling S; Huntly BJ; Beran M; Jacobsen SE; Gilliland DG. 2007. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell 12(4):367-80. [PubMed: 17936561]  [MGI Ref ID J:126003]

Additional References

Flt3^tm1Dgg related

Kharazi S; Mead AJ; Mansour A; Hultquist A; Boiers C; Luc S; Buza-Vidas N; Ma Z; Ferry H; Atkinson D; Reckzeh K; Masson K; Cammenga J; Ronnstrand L; Arai F; Suda T; Nerlov C; Sitnicka E; Jacobsen SE. 2011. Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood 118(13):3613-21. [PubMed: 21813452]  [MGI Ref ID J:177063]

Li L; Zhang L; Fan J; Greenberg K; Desiderio S; Rassool FV; Small D. 2011. Defective nonhomologous end joining blocks B-cell development in FLT3/ITD mice. Blood 117(11):3131-9. [PubMed: 21228325]  [MGI Ref ID J:170520]

Reckzeh K; Bereshchenko O; Mead A; Rehn M; Kharazi S; Jacobsen SE; Nerlov C; Cammenga J. 2012. Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model. Leukemia 26(7):1527-36. [PubMed: 22318449]  [MGI Ref ID J:190781]

Tam WF; Hahnel PS; Schuler A; Lee BH; Okabe R; Zhu N; Pante SV; Raffel G; Mercher T; Wernig G; Bockamp E; Sasca D; Kreft A; Robinson GW; Hennighausen L; Gilliland DG; Kindler T. 2013. STAT5 is crucial to maintain leukemic stem cells in acute myelogenous leukemias induced by MOZ-TIF2. Cancer Res 73(1):373-84. [PubMed: 23149921]  [MGI Ref ID J:194104]

Zorko NA; Bernot KM; Whitman SP; Siebenaler RF; Ahmed EH; Marcucci GG; Yanes DA; McConnell KK; Mao C; Kalu C; Zhang X; Jarjoura D; Dorrance AM; Heerema NA; Lee BH; Huang G; Marcucci G; Caligiuri MA. 2012. Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias. Blood 120(5):1130-6. [PubMed: 22674806]  [MGI Ref ID J:189096]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes.
Mating System	Heterozygote x +/+ sibling         (Female x Male)   15-OCT-10
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Terms of Use

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General Terms and Conditions

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