Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Coisogenic; Mutant Strain; Transgenic; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation N?+N1F2pN1 Generation Definitions   Donating Investigator Daniel Tenen,   Beth Israel Deaconess Medical Center

Description
Hemizygotes are viable, fertile, normal in size, and do not display any behavioral abnormalities. Transgene expression is directed by the tetracycline-responsive element (TRE; tetO). When hemizygotes are bred with another transgenic mouse expressing either reverse tetracycline-controlled transactivator protein (rtTA) or tetracycline-controlled transactivator protein (tTA) under the regulation of tissue-specific promoters , BCR-ABL1 fusion protein expression can be regulated in the appropriate tissue of the bitransgenic offspring with the tetracycline analog, doxycycline.

These mice originally were designed to be bred with transgenic mice harboring a Tal1-tTA transgene (see Stock No. 006209), creating double transgenic offspring as a model for studies of the Philadelphia chromosome and inducible chronic myeloid leukemia.

When bred to a strain expressing tTA in the epithelial cells of secretory organs and skin (see Stock No. 002618 - Tg(MMTVtTa)1Mam), this mutant mouse strain may be useful in studies of leukemia.

Development
A transgene was generated containing a human p210 BCR-ABL1 fusion protein cDNA sequence under transcriptional control of the tetracycline-responsive element (TRE; tetO) sequence fused to a minimal cytomegalovirus (hCMV) promoter. The transgene was injected into fertilized FVB/N eggs. Transgenic offspring (founder line 2) were maintained by breeding transgenic mice to either FVB/N inbred mice or wildtype siblings for many generations prior to arrival at The Jackson Laboratory.

Control Information

	Control
	Noncarrier
	001800 FVB/NJ
Considerations for Choosing Controls

Additional Web Information

Tet Expression Systems

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Leukemia, Chronic Myeloid; CML

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Tg(tetO-BCR/ABL1)2Dgt/0 Tg(MMTVtTA)1Mam/0

        involves: C57BL/6 * FVB/N * SJL

• life span-post-weaning/aging
• premature death
  • upon withdrawal of tetracycline (TET), expression of BCR/ABL results in development of lethal leukemia; 100% of bitransgenic mice die by ~27 days   (MGI Ref ID J:72377)
• hematopoietic system phenotype
• anemia
  • severe anemia develops in peripheral blood without TET treatment   (MGI Ref ID J:72377)
• decreased platelet cell number
  • severe thrombocytopenia in peripheral blood develops when TET treatment is stopped   (MGI Ref ID J:72377)
• enlarged spleen
  • spleen becomes massively enlarged when TET treatment is stopped   (MGI Ref ID J:72377)
• increased leukocyte cell number
  • increased peripheral blood leukocyte count is observed 6-10 days after TET withdrawal; blood shows presence of cells resembling immature lymphocytes   (MGI Ref ID J:72377)
  • when TET is given to mice in advanced stages of disease, WBC counts normalize in 48-72 hours, lymphoblasts are not detected in peripheral blood   (MGI Ref ID J:72377)
• immune system phenotype
• enlarged lymph nodes
  • nodes become massively enlarged when TET is stopped; when TET is given to mice in advanced stages of disease, complete regression of enlarged lymph nodes occurs within 5 days   (MGI Ref ID J:72377)
• enlarged spleen
  • spleen becomes massively enlarged when TET treatment is stopped   (MGI Ref ID J:72377)
• increased leukocyte cell number
  • increased peripheral blood leukocyte count is observed 6-10 days after TET withdrawal; blood shows presence of cells resembling immature lymphocytes   (MGI Ref ID J:72377)
  • when TET is given to mice in advanced stages of disease, WBC counts normalize in 48-72 hours, lymphoblasts are not detected in peripheral blood   (MGI Ref ID J:72377)
• cellular phenotype
• increased apoptosis
  • spleen becomes massively enlarged   (MGI Ref ID J:72377)
• skeleton phenotype
• abnormal bone marrow morphology
  • bone marrow is pale; hematopoietic cells are replaced by lymphoblasts   (MGI Ref ID J:72377)
• tumorigenesis
• leukemia
  • 100% of mice develop acute lymphoblastic leukemia (ALL) upon withdrawal of tetracycline administration   (MGI Ref ID J:72377)
  • leukocyte counts range from 80000-150000/ul   (MGI Ref ID J:72377)
  • leukemic cells infiltrate skin, pleura, and meninges   (MGI Ref ID J:72377)

Tg(tetO-BCR/ABL1)2Dgt/0 Tg(Tal1-tTA)19Dgt/0

        involves: C57BL/6 * DBA/2 * FVB/N

• life span-post-weaning/aging
• premature death   (MGI Ref ID J:96511)
• hematopoietic system phenotype
• abnormal hematopoiesis
  • 12 days after BCR/ABL induction, bone marrow shows a 7-fold increase in hematopoietic stem cells and a 26-fold increase after 21 days; at both points, granulocyte-macrophage progenitor (GMP) percentage is increased 3-fold, while megakaryocyte-erythroid progenitors (MEP) show a 3-fold decrease   (MGI Ref ID J:96511)
• abnormal common myeloid progenitor cell morphology
  • common myeloid precursors (CMP) show a 2-fold decrease and a 1.5-fold increase at 12 and 21 days, respectively   (MGI Ref ID J:96511)
• abnormal lymphopoiesis
  • some mice (31%) show progression to lymphoid blast crisis with lymph node enlargement and lymphoblasts in peripheral blood; lymphooblasts are found to be arrested at different maturation stages   (MGI Ref ID J:96511)
• increased leukocyte cell number
  • absolute number is increased 2-fold in peripheral blood 2 weeks after tet withdrawal (BCR/ABL induction)   (MGI Ref ID J:96511)
  • readministration of tet results in reversion of leukocytosis in approximately ~4 days   (MGI Ref ID J:96511)
• increased neutrophil cell number
  • percentage and absolute number of neutrophils are increased 3- and 5- fold in peripheral blood 2 weeks after tetracycline (tet) withdrawal compared to wild-type or single transgenic mice   (MGI Ref ID J:96511)
  • readministration of tet results in reversion of neutrophilia in approximately ~4 days   (MGI Ref ID J:96511)
• abnormal myeloblast morphology/development
  • bone marrow contains increased ratio of myeloid and erythroid cells dominated by granulocytic forms   (MGI Ref ID J:96511)
  • increase in immature myeloid cells is observed   (MGI Ref ID J:96511)
• abnormal lymphopoiesis
  • some mice (31%) show progression to lymphoid blast crisis with lymph node enlargement and lymphoblasts in peripheral blood; lymphooblasts are found to be arrested at different maturation stages   (MGI Ref ID J:96511)
• abnormal spleen red pulp morphology
  • after induction of BCR/ABL expression, expansion of spleen red pulp by granulocytic myeloid cells is observed at various time points   (MGI Ref ID J:96511)
• abnormal splenic cell ratio
  • induction of BCR/ABL increases numbers of erythroid and granulocytic-monocytic progenitor cells in spleen   (MGI Ref ID J:96511)
• enlarged spleen
  • after induction by withdrawal of tet treatment, splenomegaly invariably results   (MGI Ref ID J:96511)
  • readministration of tet results in disappearance of palpable splenomegaly   (MGI Ref ID J:96511)
• increased bone marrow cell number
  • bone marrow of diseased mice is hypercellular   (MGI Ref ID J:96511)
  • increased numbers of cells of lymphoid and myeloid lineage are detected in diseased mice   (MGI Ref ID J:96511)
• increased hematopoietic stem cell number
  • 12 days after BCR/ABL induction, bone marrow shows a 7-fold increase in hematopoietic stem cells   (MGI Ref ID J:96511)
• increased megakaryocyte cell number
  • increased numbers of megakaryocytes are detected in bone marrow and spleen of diseased mice   (MGI Ref ID J:96511)
• immune system phenotype
• abnormal lymph node morphology
  • infiltration by myeloid cells is observed   (MGI Ref ID J:96511)
• abnormal lymphopoiesis
  • some mice (31%) show progression to lymphoid blast crisis with lymph node enlargement and lymphoblasts in peripheral blood; lymphooblasts are found to be arrested at different maturation stages   (MGI Ref ID J:96511)
• abnormal spleen red pulp morphology
  • after induction of BCR/ABL expression, expansion of spleen red pulp by granulocytic myeloid cells is observed at various time points   (MGI Ref ID J:96511)
• abnormal splenic cell ratio
  • induction of BCR/ABL increases numbers of erythroid and granulocytic-monocytic progenitor cells in spleen   (MGI Ref ID J:96511)
• enlarged spleen
  • after induction by withdrawal of tet treatment, splenomegaly invariably results   (MGI Ref ID J:96511)
  • readministration of tet results in disappearance of palpable splenomegaly   (MGI Ref ID J:96511)
• increased leukocyte cell number
  • absolute number is increased 2-fold in peripheral blood 2 weeks after tet withdrawal (BCR/ABL induction)   (MGI Ref ID J:96511)
  • readministration of tet results in reversion of leukocytosis in approximately ~4 days   (MGI Ref ID J:96511)
• increased neutrophil cell number
  • percentage and absolute number of neutrophils are increased 3- and 5- fold in peripheral blood 2 weeks after tetracycline (tet) withdrawal compared to wild-type or single transgenic mice   (MGI Ref ID J:96511)
  • readministration of tet results in reversion of neutrophilia in approximately ~4 days   (MGI Ref ID J:96511)
• liver/biliary system phenotype
• enlarged liver
  • infiltration of liver by myeloid cells is observed after induction; 57% of mice display hepatomegaly   (MGI Ref ID J:96511)
• respiratory system phenotype
• abnormal lung morphology
  • infiltration by myeloid cells is observed, occasionally resulting in focal pulmonary hemorrhages   (MGI Ref ID J:96511)
• digestive/alimentary phenotype
• abnormal small intestine morphology
  • infiltration of lamina propria by myeloid cells is observed   (MGI Ref ID J:96511)
• tumorigenesis
• lymphoma
  • some mice develop lymphomas   (MGI Ref ID J:96511)
  • readministration of tet results in disappearance of lymphomas (except in 1 case)   (MGI Ref ID J:96511)
• sarcoma
  • 2 animals with fulminant disease displayed skin chloromas (granulocytic sarcomas)   (MGI Ref ID J:96511)

View Research Applications

Research Applications

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

Cancer Research
Chronic Myelogenous Leukemia
Increased Tumor Incidence
      Leukemia: lymphocytic

Hematological Research
Hematopoietic Defects
Immunological Defects

Immunology and Inflammation Research
Lymphoid Tissue Defects
      hematopoietic development
      myeloid hyperplasia

Research Tools
Cancer Research
      Leukemia
      Tetop Tet System
      myeloma and hybridoma production
Hematological Research
Tet Expression Systems
      tTA/rtTA Responsive Strains

Genes & Alleles

Gene & Allele Information

Allele Symbol		Tg(tetO-BCR/ABL1)2Dgt
Allele Name		transgene insertion 2, Daniel G Tenen
Allele Type		Transgenic (random, expressed)
Common Name(s)		BCR-ABL1; TRE-BCR-ABL; TRE-BCR/ABL; TRE-P10 BCR/ABL; Tg(BCR/ABL1)2Dgt; Tg(BCR/ABL1)3Dgt; p210 BCR-ABL1 transponder;
Mutation Made By		Daniel Tenen,   Beth Israel Deaconess Medical Center
Strain of Origin		FVB/N
Expressed Gene		BCR, breakpoint cluster region, human
General Note		This record is also representative of lines 3 and 4 that were also generated; all of these lines exhibit a similar phenotype in combination with Tg(MMTVtTA)1Mam.Bitransgenic mice with this transgene in combination with Tg(MMTVtTA)1Mam, when tetracycline administration is stopped, are models for B cell acute lymphoblastic leukemia (ALL); line 2 exhibits the greatest leukemia susceptibility (Figure 1). (J:72377)
Molecular Note		The transgene contains a cDNA encoding the human p210 BCR-ABL1 fusion protein (B3A2 form; J:86227) under transcriptional control of the tetracycline-responsive element (tetO; also called TRE) fused to a minimal cytomegalovirus (CMV) promoter. In doubly transgenic mice expressing a tetracycline transactivator or reverse transactivator protein under control of a ubiquitous or tissue-specific promoter, expression of the BCL-ABL1 fusion gene can be controlled temporally by withdrawal or administration of a tetracycline analog. [MGI Ref ID J:72377]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(tetO-BCR/ABL1)2Dgt, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References

Selected Reference(s)

Huettner CS; Zhang P; Van Etten RA; Tenen DG. 2000. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 24(1):57-60. [PubMed: 10615128]  [MGI Ref ID J:72377]

Additional References

Tg(tetO-BCR/ABL1)2Dgt related

Huettner CS; Koschmieder S; Iwasaki H; Iwasaki-Arai J; Radomska HS; Akashi K; Tenen DG. 2003. Inducible expression of BCR/ABL using human CD34 regulatory elements results in a megakaryocytic myeloproliferative syndrome. Blood 102(9):3363-70. [PubMed: 12855552]  [MGI Ref ID J:86227]

Koschmieder S; Gottgens B; Zhang P; Iwasaki-Arai J; Akashi K; Kutok JL; Dayaram T; Geary K; Green AR; Tenen DG; Huettner CS. 2005. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood 105(1):324-34. [PubMed: 15331442]  [MGI Ref ID J:96511]

Tilli MT; Furth PA. 2003. Conditional mouse models demonstrate oncogene-dependent differences in tumor maintenance and recurrence. Breast Cancer Res 5(4):202-5. [PubMed: 12817992]  [MGI Ref ID J:84503]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, transgenic mice are bred together or to wildtype siblings.

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Noncarrier
	001800 FVB/NJ
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

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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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