Overview

These transgenic mice express the human MCL1 under the direction of the human endogenous promoter. Mice exhibit enlarged spleens, increased total splenocyte number, lymph node enlargement and a high probability of developing lymphomas. This transgenic mouse strain may be useful in studies related to tumorigenesis and inhibition of tumorigenesis in the presence of a viability-promoting BCL2 family member.

Donating Investigator

Ruth W. Craig, Dartmouth Medical School

Genetic overview

Genetic Background	Generation

Tg(MCL1)8Caig

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

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Research Applications

Cancer Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

These transgenic mice express the human MCL1 under the direction of the human MCL1 promoter. Expression of the human MCL1 protein was immunodetectable. Mice hemizygous for the transgene exhibited human MCL1 in bone marrow, lymph node, thymus and spleen (both B- and T-cell populations). Low levels of transgene expression was found in kidney, small intestine, uterus, lung and liver. The majority of the transgenic mice had enlarged spleens, with an increased total splenocyte number (both B- and T-cell). Transgenic mice displayed an increase of myeloid cells relative to lymphoid cells in bone marrow, and an enhanced viability of hematopoietic and lymphoid cells (B, T and myeloid) at immature and mature stages of development. In transgenic mice from 6 to 11 months of age, 27% displayed lymph node enlargement. Transgenic mice had an 88% probability of developing pathologic lymph node disease, and a 60% probability of developing disseminated disease from 6 months to 2 years of age. The lymphomas in the transgenic mice were predominantly of clonal B-cell origin and displayed a variety of histological subtypes including follicular lymphoma and diffuse large-cell lymphoma. This transgenic mouse strain represents a model that may be useful in studies related to tumorigenesis and inhibition of tumorigenesis in the presence of a viability-promoting BCL2 family member.

Development

A transgenic construct containing the entire human MCL1 gene, including the endogenous MCL1 promoter, was microinjected into B6;SJLF1 fertilized oocytes. Founder animals were bred to C57BL/6J mice.

Expression Data

Expressed Gene	MCL1, MCL1, BCL2 family apoptosis regulator, human
Site of Expression

Selected References

Zhou P; Qian L; Bieszczad CK; Noelle R; Binder M; Levy NB; Craig RW. 1998. Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood 92(9):3226-39PubMed: 9787159 MGI: J:50604

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Genetics

Tg(MCL1)8Caig

Allele Symbol: Tg(MCL1)8Caig

Allele Name	transgene insertion 8, Ruth W Craig
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)
Gene Symbol and Name	Tg(MCL1)8Caig, transgene insertion 8, Ruth W Craig
Gene Synonym(s)
Promoter	MCL1, MCL1, BCL2 family apoptosis regulator, human
Expressed Gene	MCL1, MCL1, BCL2 family apoptosis regulator, human
Strain of Origin	(C57BL/6 x SJL)F1
Chromosome	UN
Molecular Note	The transgene contains the entire human MCL1 gene, including the endogenous MCL1 promoter. Hemizygous transgenic mice expressed human MCL1 in bone marrow, lymph node, thymus, and spleen (both B- and T-cell populations). Low levels of transgene expression were found in the kidney, small intestine, uterus, lung and liver.
Mutations Made By	Ruth Craig, Dartmouth Medical School

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cancer Research
- Increased Tumor Incidence
  - Lymphomas

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Tg(MCL1)8Caig/0
involves: C57BL/6 * SJL

cellular phenotype

abnormal macrophage apoptosis
- bone marrow derived macrophages have significantly less apoptosis than controls 20 hours after infection with pneumococcal infection
- by 48 hours after infection, apoptosis levels are similar to that in wild-type controls suggesting pneumococcal-associated apoptosis is delayed rather than suppressed

decreased splenocyte apoptosis
- 25% of splenocytes survive four days of culture while all of controls die
- cultured splenocytes die off at a rate about half that of controls

abnormal mast cell differentiation
- immortalized immature mast cells can be cultured out of spleens with a frequency of 3 x 10^-5, which is at least 1000-fold more frequent than controls

decreased T cell apoptosis
- T cells are still present after 3 days of splenocyte culture compared to no T cells surviving culture of wild-type splenocytes

abnormal monocyte differentiation
- immortalized monocytes can be cultured of out of spleens unlike with wild-type controls

decreased B cell apoptosis
- B cells present in splenocyte culture die-off at about half the rate as wild-type B cells do

endocrine/exocrine gland phenotype

increased thymocyte number
- 2 of 9 mice have increased numbers of thymocytes

increased T cell derived lymphoma incidence
- non-disseminated T cell lymphoma occurred in 1 case out of 18 total lymphoma cases

growth/size/body region phenotype

spleen hyperplasia
- spleens have 1.6-fold higher number of cells and are visibly larger

hematopoietic system phenotype

abnormal common myeloid progenitor cell morphology
- these progenitors exhibit enhanced survival in the absence of growth factors
- there is a doubling in the number of myeloid progenitors found in the bone marrow

abnormal immature B cell morphology
- however, there is a 5-fold increase in the number of B cell precursors found in bone marrow culture compared to controls
- ratio of myeloid to B cell precursors is 2.2:1 versus 1.3:1 in wild-type bone marrow

abnormal mast cell differentiation
- immortalized immature mast cells can be cultured out of spleens with a frequency of 3 x 10^-5, which is at least 1000-fold more frequent than controls

abnormal monocyte differentiation
- immortalized monocytes can be cultured of out of spleens unlike with wild-type controls

decreased T cell apoptosis
- T cells are still present after 3 days of splenocyte culture compared to no T cells surviving culture of wild-type splenocytes

spleen hyperplasia
- spleens have 1.6-fold higher number of cells and are visibly larger

extramedullary hematopoiesis
- extramedullary hematopoiesis is very active in these mice

increased spleen white pulp amount
- mice rarely have expansion of the white pulp

abnormal macrophage apoptosis
- by 48 hours after infection, apoptosis levels are similar to that in wild-type controls suggesting pneumococcal-associated apoptosis is delayed rather than suppressed
- bone marrow derived macrophages have significantly less apoptosis than controls 20 hours after infection with pneumococcal infection

decreased splenocyte apoptosis
- cultured splenocytes die off at a rate about half that of controls
- 25% of splenocytes survive four days of culture while all of controls die

abnormal leukocyte physiology
- including IL-3 in the culture greatly enhanced survival of transgenic myeloid cells but not non-transgenic myeloid cells
- myeloid cells present in splenocyte culture die-off at a slower rate than controls

increased thymocyte number
- 2 of 9 mice have increased numbers of thymocytes

decreased B cell apoptosis
- B cells present in splenocyte culture die-off at about half the rate as wild-type B cells do

increased erythroid progenitor cell number
- there is a doubling in the number of erythroid progenitors found in the bone marrow
- these progenitors exhibit enhanced survival in the absence of growth factors

immune system phenotype

increased spleen white pulp amount
- mice rarely have expansion of the white pulp

increased susceptibility to bacterial infection
- mice fail to clear bacteria after infection with 10⁴ CFU compared to controls
- pneumococcal-associated macrophage apoptosis is lower by about half in these mice 14 hours after infection
- all transgenic mice with more than 10² CFU in the lung develope bacteremia, which does not occur in nontransgenic mice
- at higher infection doses, the amount of CFUs in the lung is a log unit higher than that in wild-type mice

abnormal macrophage apoptosis
- by 48 hours after infection, apoptosis levels are similar to that in wild-type controls suggesting pneumococcal-associated apoptosis is delayed rather than suppressed
- bone marrow derived macrophages have significantly less apoptosis than controls 20 hours after infection with pneumococcal infection

abnormal immature B cell morphology
- ratio of myeloid to B cell precursors is 2.2:1 versus 1.3:1 in wild-type bone marrow
- however, there is a 5-fold increase in the number of B cell precursors found in bone marrow culture compared to controls

decreased splenocyte apoptosis
- 25% of splenocytes survive four days of culture while all of controls die
- cultured splenocytes die off at a rate about half that of controls

abnormal leukocyte physiology
- including IL-3 in the culture greatly enhanced survival of transgenic myeloid cells but not non-transgenic myeloid cells
- myeloid cells present in splenocyte culture die-off at a slower rate than controls

abnormal mast cell differentiation
- immortalized immature mast cells can be cultured out of spleens with a frequency of 3 x 10^-5, which is at least 1000-fold more frequent than controls

abnormal monocyte differentiation
- immortalized monocytes can be cultured of out of spleens unlike with wild-type controls

decreased T cell apoptosis
- T cells are still present after 3 days of splenocyte culture compared to no T cells surviving culture of wild-type splenocytes

increased thymocyte number
- 2 of 9 mice have increased numbers of thymocytes

decreased B cell apoptosis
- B cells present in splenocyte culture die-off at about half the rate as wild-type B cells do

spleen hyperplasia
- spleens have 1.6-fold higher number of cells and are visibly larger

neoplasm

increased follicular lymphoma incidence
- Ig-heavy chain analysis of lymphomas reveals clonal rearrangement of the immunoglobulin heavy-chain locus (except in the one case of T cell lymphoma) demonstrating a B cell origin
- B cells lacking IgM expression constitute the majority of the large cells in the cases of disseminated disease
- the majority of lymphomas are diffuse large-cell lymphoma with B-cell origins or indeterminate origin
- some cases present a polymorphic cytology consisting of a heterogeneous mixture of small and large lymphocytes

increased T cell derived lymphoma incidence
- non-disseminated T cell lymphoma occurred in 1 case out of 18 total lymphoma cases

increased lymphoma incidence
- two-thirds of the cases involve disseminated disease affecting lymph nodes (mesenteric, renal, mediastinal, and cervical areas) and other tissues (liver, lung, kidney)
- lymphomas develop in about 50% of transgenic mice at 18 to 23 months of age and in about 65% of mice at 2 years of age compared to 12% of non-transgenic mice by 2 years of age
- in the remaining one third of affected transgenic animals, disease was localized to mesenteric lymph nodes or presented as extra-nodal lymphoma in the gastrointestinal tract
- about 27% of mice at 6-11 months of age develop lymphomas of various subtypes

References

Zhou P; Qian L; Bieszczad CK; Noelle R; Binder M; Levy NB; Craig RW. 1998. Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood 92(9):3226-39PubMed: 9787159 MGI: J:50604

Additional References

Zhou P; Levy NB; Xie H; Qian L; Lee CY; Gascoyne RD; Craig RW. 2001. MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood 97(12):3902-9PubMed: 11389033 MGI: J:69755

Additional - Tg(MCL1)8Caig related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Tg(MCL1)8Caig-alternate1
- Genotyping resources and troubleshooting
Breeding Considerations

This transgenic strain was created on a B6;SJLF1 background. Founder animals were bred to normal C57BL/6J mice to produce hemizygotes. These mice are maintained by mating hemizygotes. Female homozygotes are fertile and do not mate.
- Additional Breeding and Husbandry Support
Citation
When using the B6;SJL-Tg(MCL1)8Caig/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #004187 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
> >	Hemizygous or Non carrier for Tg(MCL1)8Caig

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Selected References

Tg(MCL1)8Caig

Allele Symbol: Tg(MCL1)8Caig

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Tg(MCL1)8Caig/0involves: C57BL/6 * SJL

cellular phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

hematopoietic system phenotype

immune system phenotype

neoplasm

References

Additional References

Additional - Tg(MCL1)8Caig related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Genotype: Tg(MCL1)8Caig/0
involves: C57BL/6 * SJL