Strain Name:

B6.Cg-Tg(MCL1)8Caig/Mmjax

Availability:

Repository- Live     Available at the JAX MMRRC

Please refer to the Mutant Mouse Regional Resource Center (MMRRC) for information about B6(SJL)-Tg(MCL1)8Caig/Mmjax MMRRC Stock Number 036764.
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.

Description

Strain Information

Type Congenic; Mutant Strain; Transgenic;
Additional information on Genetically Engineered and Mutant Mice.
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Mating SystemHemizygote x Noncarrier         (Female x Male)   11-AUG-14
Specieslaboratory mouse
 
Donating Investigator Ruth W. Craig,   Dartmouth Medical School

Development
A transgenic construct containing the entire human MCL1 gene, including the endogenous promoter, was microinjected into B6;SJLF1 fertilized oocytes. The donating investigator reports that founder line 8 was established and backcrossed to C57BL/6NTac for more than 10 generations (see SNP note below). Upon arrival, transgenic mice were bred to C57BL/6NJ inbred mice (Stock No. 005304) for at least one generation 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
   Noncarrier
   005304 C57BL/6NJ
 
  Considerations for Choosing Controls

Related Strains

Strains carrying   Tg(MCL1)8Caig allele
004187   B6;SJL-Tg(MCL1)8Caig/J
View Strains carrying   Tg(MCL1)8Caig     (1 strain)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

The following phenotype information is associated with a similar, but not exact match to this JAX® Mice strain.

Tg(MCL1)8Caig/0

        involves: C57BL/6 * SJL
  • immune system phenotype
  • 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   (MGI Ref ID J:50604)
    • however, there is a 5-fold increase in the number of B cell precursors found in bone marrow culture compared to controls   (MGI Ref ID J:50604)
  • abnormal leukocyte physiology
    • myeloid cells present in splenocyte culture die-off at a slower rate than controls   (MGI Ref ID J:50604)
    • including IL-3 in the culture greatly enhanced survival of transgenic myeloid cells but not non-transgenic myeloid cells   (MGI Ref ID J:50604)
    • abnormal macrophage apoptosis
      • bone marrow derived macrophages have significantly less apoptosis than controls 20 hours after infection with pneumococcal infection   (MGI Ref ID J:95913)
      • by 48 hours after infection, apoptosis levels are similar to that in wild-type controls suggesting pneumococcal-associated apoptosis is delayed rather than suppressed   (MGI Ref ID J:95913)
    • decreased B cell apoptosis
      • B cells present in splenocyte culture die-off at about half the rate as wild-type B cells do   (MGI Ref ID J:50604)
    • 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   (MGI Ref ID J:50604)
  • 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   (MGI Ref ID J:50604)
  • abnormal monocyte differentiation
    • immortalized monocytes can be cultured of out of spleens unlike with wild-type controls   (MGI Ref ID J:50604)
  • decreased splenocyte apoptosis
    • 25% of splenocytes survive four days of culture while all of controls die   (MGI Ref ID J:50604)
    • cultured splenocytes die off at a rate about half that of controls   (MGI Ref ID J:50604)
  • increased spleen white pulp amount
    • mice rarely have expansion of the white pulp   (MGI Ref ID J:50604)
  • increased susceptibility to bacterial infection
    • pneumococcal-associated macrophage apoptosis is lower by about half in these mice 14 hours after infection   (MGI Ref ID J:95913)
    • mice fail to clear bacteria after infection with 104 CFU compared to controls   (MGI Ref ID J:95913)
    • all transgenic mice with more than 102 CFU in the lung develope bacteremia, which does not occur in nontransgenic mice   (MGI Ref ID J:95913)
    • at higher infection doses, the amount of CFUs in the lung is a log unit higher than that in wild-type mice   (MGI Ref ID J:95913)
  • increased thymocyte number
    • 2 of 9 mice have increased numbers of thymocytes   (MGI Ref ID J:50604)
  • spleen hyperplasia
    • spleens have 1.6-fold higher number of cells and are visibly larger   (MGI Ref ID J:50604)
  • hematopoietic system phenotype
  • abnormal common myeloid progenitor cell morphology   (MGI Ref ID J:69755)
    • there is a doubling in the number of myeloid progenitors found in the bone marrow   (MGI Ref ID J:50604)
    • these progenitors exhibit enhanced survival in the absence of growth factors   (MGI Ref ID J:50604)
  • 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   (MGI Ref ID J:50604)
    • however, there is a 5-fold increase in the number of B cell precursors found in bone marrow culture compared to controls   (MGI Ref ID J:50604)
  • abnormal leukocyte physiology
    • myeloid cells present in splenocyte culture die-off at a slower rate than controls   (MGI Ref ID J:50604)
    • including IL-3 in the culture greatly enhanced survival of transgenic myeloid cells but not non-transgenic myeloid cells   (MGI Ref ID J:50604)
    • abnormal macrophage apoptosis
      • bone marrow derived macrophages have significantly less apoptosis than controls 20 hours after infection with pneumococcal infection   (MGI Ref ID J:95913)
      • by 48 hours after infection, apoptosis levels are similar to that in wild-type controls suggesting pneumococcal-associated apoptosis is delayed rather than suppressed   (MGI Ref ID J:95913)
    • decreased B cell apoptosis
      • B cells present in splenocyte culture die-off at about half the rate as wild-type B cells do   (MGI Ref ID J:50604)
    • 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   (MGI Ref ID J:50604)
  • 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   (MGI Ref ID J:50604)
  • abnormal monocyte differentiation
    • immortalized monocytes can be cultured of out of spleens unlike with wild-type controls   (MGI Ref ID J:50604)
  • decreased splenocyte apoptosis
    • 25% of splenocytes survive four days of culture while all of controls die   (MGI Ref ID J:50604)
    • cultured splenocytes die off at a rate about half that of controls   (MGI Ref ID J:50604)
  • extramedullary hematopoiesis
    • extramedullary hematopoiesis is very active in these mice   (MGI Ref ID J:50604)
  • increased erythroid progenitor cell number
    • there is a doubling in the number of erythroid progenitors found in the bone marrow   (MGI Ref ID J:50604)
    • these progenitors exhibit enhanced survival in the absence of growth factors   (MGI Ref ID J:50604)
  • increased spleen white pulp amount
    • mice rarely have expansion of the white pulp   (MGI Ref ID J:50604)
  • increased thymocyte number
    • 2 of 9 mice have increased numbers of thymocytes   (MGI Ref ID J:50604)
  • spleen hyperplasia
    • spleens have 1.6-fold higher number of cells and are visibly larger   (MGI Ref ID J:50604)
  • tumorigenesis
  • increased lymphoma incidence
    • about 27% of mice at 6-11 months of age develop lymphomas of various subtypes   (MGI Ref ID J:69755)
    • 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   (MGI Ref ID J:69755)
    • two-thirds of the cases involve disseminated disease affecting lymph nodes (mesenteric, renal, mediastinal, and cervical areas) and other tissues (liver, lung, kidney)   (MGI Ref ID J:69755)
    • 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   (MGI Ref ID J:69755)
    • increased T cell derived lymphoma incidence
      • non-disseminated T cell lymphoma occurred in 1 case out of 18 total lymphoma cases   (MGI Ref ID J:69755)
    • increased follicular lymphoma incidence
      • the majority of lymphomas are diffuse large-cell lymphoma with B-cell origins or indeterminate origin   (MGI Ref ID J:69755)
      • some cases present a polymorphic cytology consisting of a heterogeneous mixture of small and large lymphocytes   (MGI Ref ID J:69755)
      • B cells lacking IgM expression constitute the majority of the large cells in the cases of disseminated disease   (MGI Ref ID J:69755)
      • 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   (MGI Ref ID J:69755)
  • cellular phenotype
  • abnormal macrophage apoptosis
    • bone marrow derived macrophages have significantly less apoptosis than controls 20 hours after infection with pneumococcal infection   (MGI Ref ID J:95913)
    • by 48 hours after infection, apoptosis levels are similar to that in wild-type controls suggesting pneumococcal-associated apoptosis is delayed rather than suppressed   (MGI Ref ID J:95913)
  • 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   (MGI Ref ID J:50604)
  • abnormal monocyte differentiation
    • immortalized monocytes can be cultured of out of spleens unlike with wild-type controls   (MGI Ref ID J:50604)
  • decreased B cell apoptosis
    • B cells present in splenocyte culture die-off at about half the rate as wild-type B cells do   (MGI Ref ID J:50604)
  • 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   (MGI Ref ID J:50604)
  • decreased splenocyte apoptosis
    • 25% of splenocytes survive four days of culture while all of controls die   (MGI Ref ID J:50604)
    • cultured splenocytes die off at a rate about half that of controls   (MGI Ref ID J:50604)
  • endocrine/exocrine gland phenotype
  • increased thymocyte number
    • 2 of 9 mice have increased numbers of thymocytes   (MGI Ref ID J:50604)
View Research Applications

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

Cancer Research
Increased Tumor Incidence
      Lymphomas

MCL1 related

Apoptosis Research
Endogenous Regulators

Cancer Research
Increased Tumor Incidence
      Leukemia

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Tg(MCL1)8Caig
Allele Name transgene insertion 8, Ruth W Craig
Allele Type Transgenic (Inserted expressed sequence)
Mutation Made By Ruth Craig,   Dartmouth Medical School
Strain of Origin(C57BL/6 x SJL)F1
Expressed Gene MCL1, myeloid cell leukemia 1, human
Promoter MCL1, myeloid cell leukemia 1, human
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. [MGI Ref ID J:50604]
 

Genotyping

Genotyping Information

Genotyping Protocols

Tg(MCL1)8Caig-alternate1, Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

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):3226-39. [PubMed: 9787159]  [MGI Ref ID J:50604]

Additional References

Tg(MCL1)8Caig related

Gui J; Morales AJ; Maxey SE; Bessette KA; Ratcliffe NR; Kelly JA; Craig RW. 2011. MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood. Int Immunol 23(10):647-59. [PubMed: 21937457]  [MGI Ref ID J:177131]

Marriott HM; Bingle CD; Read RC; Braley KE; Kroemer G; Hellewell PG; Craig RW; Whyte MK; Dockrell DH. 2005. Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. J Clin Invest 115(2):359-68. [PubMed: 15650769]  [MGI Ref ID J:95913]

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):3902-9. [PubMed: 11389033]  [MGI Ref ID J:69755]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, hemizygous mice may be bred with wildtype (noncarrier) mice from the colony or with C57BL/6NJ inbred mice (Stock No. 005304).
Mating SystemHemizygote x Noncarrier         (Female x Male)   11-AUG-14
Diet Information LabDiet® 5K52/5K67

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