Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Daniel Tenen,   Beth Israel Deaconess Medical Center

Description
Mice homozygous for this targeted deletion are viable and fertile as young animals. Mice on this stock (predominantly 129Sv) background often die between 3-8 months of age of a rapidly developing T cell lymphoma (64% penetrance) or between 6-12 months of acute myeloid lymphoma (AML) (29% penetrance). Homozygotes (termed PU.1 knockdown or UREdelta) have an 80% reduction of endogneous gene expression. This is associated with an accumulation of hematopoietic stem cell precursor cells and neutrophils in bone marrow and spleen. Bone marrow cells from homozygous mice have abnormal responses to myeloid cytokines, and malignant transformation is associated with clonal chromosomal abnormalities. Homozygous mice have abnormal B- and T-cell populations and lineage commitment. These mice may be useful in studing T cell lymphoma, AML and other cancers, transcription factors, and development of multiple cell lineages.

Of note, the latency and penetrance of disease is slightly different from those homozygous mice harboring the URE deletion (and neo cassette) on a mixed BALB/c, C57BL/6, and 129 background (see Sfpi1^tm1.1 mice described in Rosenbauer 2004 Nat Genet 36:624).

Development
A targeting vector was designed to place a loxP site on both sides of the 3.4 kb upstream regulatory element (URE) located 14 kb upstream of the endogenous gene. This also inserted a FRT-flanked PGKneo cassette immediately upstream of the loxP-flanked genome. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Chimeric mice were interbred or crossed to C57BL/6 females, resulting in mutant -14kb URE^loxP+neo (or Sfpi1^tm1Dgt) mice. These were next crossed with BALB/c mice carrying the CMV-cre transgene to excise the URE, creating UREdelta-neo (also called deltaURE-neo, Sfpi1^tm1.1). The neomycin resistance cassette was next removed by breeding heterozygous UREdelta-neo mutants on a mixed (but predominantly BALB/c) background with 129Sv mice carrying a "ROSA-FLP" transgene. The resulting offspring (on a mixed, but predominantly 129Sv, background) with the endogenous -14kb upstream regulatory element now replaced with a single FRT and loxP site were maintained by breeding heterozygotes prior to arrival at The Jackson Laboratory.

Control Information

	Control
	Heterozygote from the colony
	Wild-type from the colony
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Sfpi1

006922	B6.Cg-Sfpi1tm2Dgt/J
006099	B6;129-Sfpi1tm1.2Dgt/J
006147	B6;FVB-Tg(Sfpi1,-EGFP)7Dgt/J

View Strains carrying other alleles of Sfpi1     (3 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Leukemia, Acute Myeloid; AML - Models with phenotypic similarity to human disease where etiologies are distinct.2

2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Sfpi1^tm1.3Dgt/Sfpi1^tm1.3Dgt

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

• life span-post-weaning/aging
• premature death (MGI Ref ID J:106040)
  • > 90% of mice homozygous for this mutation die between 3 and 13 months of age
• tumorigenesis
• increased tumor incidence (MGI Ref ID J:106040)
  • 6.5% of homozygous mutant mice simultaneously harbor both T-cell lymphoma and acute myeloid leukemia (AML)
• T cell derived lymphoma (MGI Ref ID J:106040)
  • in 40% of mice with thymic lymphoma, lymphoma cells are present in the periphery where they greatly elevate peripheral blood lymphocyte numbers, form spleen and/or lymph node tumors, and invade nonhematopoietic organs
  • T-cell lymphoma cells of homozygous mutant mice vary in their expression of CD4 and CD8 and are CD3^dim
  • lymphoma cells of mutant mice express terminal deoxynucleotide transferase, a characteristic of immature T lymphoblast cells
  • the lymphoma cells, unlike ordinary T-cell progenitor cells in these mice, express only low levels of PU.1/SFPI1
  • analysis of the TCR-beta variable-region isotype of T-cell lymphoma cells from lymph node tumors indicates they are clonally derived
  • a characteristic pattern of promoter hypermethylation is detected by RLGS analysis in T-cell lymphomas (but not in myeloid tumors) of homozygous mutant mice
  • hypermethylation and transcriptional downregulation of the inhibitor of DNA binding 4 (Id4) tumor suppressor gene is characteristic of T-cell lymphomas, but not of myeloid tumors, of homozygous mutant mice
  • T-cell lymphomas of these mice exhibit a characteristic pattern of promoter hypermethylation that is not shared by myeloid tumors in the same mice; inhibitor of DNA binding 4 (Id4, aka Idb4) is reproducibly hypermethylated and downregulated in these but not AML
  • injection of lymphoma cells transmits the phenoytpe to NOD.CB17-Prkdc^scid mice, causing death within 3-6 weeks
• leukemia (MGI Ref ID J:106040)
  • between 6 and 12 months of age, 29.0% of homozygous mice develop acute myeloid leukemia (AML)
• thymic lymphoma (MGI Ref ID J:106040)
  • between 3 and 8 months of age, 64.5% of mutant mice develop massive tumors of the thymus
• immune system phenotype
• abnormal T cell subpopulation ratio (MGI Ref ID J:106040)
  • the proportion of immature, CD4^-CD8^- (double negative, DN) thymocytes is elevated
  • within the DN thymocyte population, the proportions of early, DN1-DN2 stage thymocytes are elevated, while later, DN3-DN4 stage thymocyte percentages are reduced
  • mutant thymi contain elevated numbers of the earliest T cell lineage-restricted progenitor cells (ETPs, CD3^-CD4^-CD8^-Kit^bright), but reduced numbers of proT and preT cells
• abnormal double-negative T cell morphology (MGI Ref ID J:106040)
  • SFPI1/PU.1 is expressed at higher levels in mutant than in wild-type ETPs and DN1-DN3 thymocytes, but is turned off in both mutant and wild-type CD4⁺CD8⁺ (double positive, DP) thymocytes
• arrested B cell differentiation (MGI Ref ID J:106040)
  • B cell differentiation is blocked before the pro-B cell stage in mutant mice, as numbers of bone marrow pro-B cells (Lin^-IgM^-B220⁺CD43⁺) and pre-B cells (Lin^-IgM^-B220⁺CD43^-) are greatly reduced
• decreased T cell number (MGI Ref ID J:106040)
  • numbers of mature CD4⁺ and CD8⁺ T cells in the periphery are slightly reduced in mutant mice
• decreased thymocyte number (MGI Ref ID J:106040)
  • thymi of mutant mice contain 3.4-fold fewer thymocytes than those of wild-type mice
• decreased granulocyte number (MGI Ref ID J:106040)
  • proportion of myeloid cells (Mac1^lowIgm^-) in the peritoneum diminishes over time
• decreased mature B cell number (MGI Ref ID J:106040)
  • mature B cell numbers are greatly reduced in bone marrow, spleen and liver of homozygous mutant mice
• decreased B-1a cell number (MGI Ref ID J:106040)
  • the intraperitoneal B1 cell population is skewed toward B1b cells (CD5^-), with concomitant reduction of the proportion of B1a cells (CD5⁺) from the 30-40% seen in wild-type mice to ~10-20% in homozygous mutants
• decreased pre-B cell number (MGI Ref ID J:106040)
  • numbers of bone marrow pre-B cells (Lin^-IgM^-B220⁺CD43^-) are greatly reduced
• decreased pro-B cell number (MGI Ref ID J:106040)
  • numbers of bone marrow pro-B cells (Lin^-IgM^-B220⁺CD43⁺) are greatly reduced
• increased IgM level (MGI Ref ID J:106040)
  • circulating IgM levels in mutant mice are elevated to 3-fold wild-type levels
• increased lymphocyte cell number (MGI Ref ID J:106040)
  • intraperitoneal lymphocyte numbers in mutant mice increase progressively with age, to greater than 3-fold wild-type numbers by 4-8 months
• increased B-1 B cell number (MGI Ref ID J:106040)
  • the percentage of physically and functionally normal B1 cells (Mac1^lowIgM^highCD43⁺B7.1⁺CD23^-CD19⁺B220^low) in the peritoneum increases with time
  • B1 cells account for up to 43% of peripheral blood lymphocytes in older mutant mice, although they are not present in blood of wild-type mice
  • Southern blot analysis of peritoneal lymphocytes for IghD-J rearrangements found evidence of clonal B1 cell proliferation in one mutant mouse of 6 studied at ages 6-8 mo
• increased B-1b cell number (MGI Ref ID J:106040)
  • the intraperitoneal B1 cell population is skewed toward B1b cells (CD5^-), with concomitant reduction of the proportion of B1a cells (CD5⁺) from the 30-40% seen in wild-type mice to ~10-20% in homozygous mutants
• increased T cell number (MGI Ref ID J:106040)
  • peripheral blood T-lymphocyte numbers are greatly elevated in 40% of mice with thymic lymphoma
• small thymus (MGI Ref ID J:106040)
• hematopoietic system phenotype
• abnormal T cell subpopulation ratio (MGI Ref ID J:106040)
  • the proportion of immature, CD4^-CD8^- (double negative, DN) thymocytes is elevated
  • within the DN thymocyte population, the proportions of early, DN1-DN2 stage thymocytes are elevated, while later, DN3-DN4 stage thymocyte percentages are reduced
  • mutant thymi contain elevated numbers of the earliest T cell lineage-restricted progenitor cells (ETPs, CD3^-CD4^-CD8^-Kit^bright), but reduced numbers of proT and preT cells
• abnormal double-negative T cell morphology (MGI Ref ID J:106040)
  • SFPI1/PU.1 is expressed at higher levels in mutant than in wild-type ETPs and DN1-DN3 thymocytes, but is turned off in both mutant and wild-type CD4⁺CD8⁺ (double positive, DP) thymocytes
• arrested B cell differentiation (MGI Ref ID J:106040)
  • B cell differentiation is blocked before the pro-B cell stage in mutant mice, as numbers of bone marrow pro-B cells (Lin^-IgM^-B220⁺CD43⁺) and pre-B cells (Lin^-IgM^-B220⁺CD43^-) are greatly reduced
• decreased T cell number (MGI Ref ID J:106040)
  • numbers of mature CD4⁺ and CD8⁺ T cells in the periphery are slightly reduced in mutant mice
• decreased thymocyte number (MGI Ref ID J:106040)
  • thymi of mutant mice contain 3.4-fold fewer thymocytes than those of wild-type mice
• decreased granulocyte number (MGI Ref ID J:106040)
  • proportion of myeloid cells (Mac1^lowIgm^-) in the peritoneum diminishes over time
• decreased mature B cell number (MGI Ref ID J:106040)
  • mature B cell numbers are greatly reduced in bone marrow, spleen and liver of homozygous mutant mice
• decreased B-1a cell number (MGI Ref ID J:106040)
  • the intraperitoneal B1 cell population is skewed toward B1b cells (CD5^-), with concomitant reduction of the proportion of B1a cells (CD5⁺) from the 30-40% seen in wild-type mice to ~10-20% in homozygous mutants
• decreased pre-B cell number (MGI Ref ID J:106040)
  • numbers of bone marrow pre-B cells (Lin^-IgM^-B220⁺CD43^-) are greatly reduced
• decreased pro-B cell number (MGI Ref ID J:106040)
  • numbers of bone marrow pro-B cells (Lin^-IgM^-B220⁺CD43⁺) are greatly reduced
• increased lymphocyte cell number (MGI Ref ID J:106040)
  • intraperitoneal lymphocyte numbers in mutant mice increase progressively with age, to greater than 3-fold wild-type numbers by 4-8 months
• increased B-1 B cell number (MGI Ref ID J:106040)
  • the percentage of physically and functionally normal B1 cells (Mac1^lowIgM^highCD43⁺B7.1⁺CD23^-CD19⁺B220^low) in the peritoneum increases with time
  • B1 cells account for up to 43% of peripheral blood lymphocytes in older mutant mice, although they are not present in blood of wild-type mice
  • Southern blot analysis of peritoneal lymphocytes for IghD-J rearrangements found evidence of clonal B1 cell proliferation in one mutant mouse of 6 studied at ages 6-8 mo
• increased B-1b cell number (MGI Ref ID J:106040)
  • the intraperitoneal B1 cell population is skewed toward B1b cells (CD5^-), with concomitant reduction of the proportion of B1a cells (CD5⁺) from the 30-40% seen in wild-type mice to ~10-20% in homozygous mutants
• increased T cell number (MGI Ref ID J:106040)
  • peripheral blood T-lymphocyte numbers are greatly elevated in 40% of mice with thymic lymphoma
• small thymus (MGI Ref ID J:106040)

Sfpi1^tm1.3Dgt/Sfpi1^tm1.3Dgt

        involves: 129 * BALB/c * C57BL/6

• life span-post-weaning/aging
• premature death (MGI Ref ID J:90331)
  • mice are moribund or die by 3 to 8 months from fatal, aggressive neoplastic disease
• tumorigenesis
• T cell derived lymphoma (MGI Ref ID J:90331)
  • T cell lymphomas accompany myeloid leukemia and was the dominant disease in 2 mice
• leukemia (MGI Ref ID J:90331)
  • mice develop fatal, aggressive neoplastic disease similar to AML (acute myelogenous leukemia)
• immune system phenotype
• abnormal spleen morphology (MGI Ref ID J:90331)
  • abnormal architecture due to expansion of myeloid cells
• enlarged spleen (MGI Ref ID J:90331)
  • spleen is 1.5 to 2 times bigger than in wild-type mice
• increased spleen weight (MGI Ref ID J:90331)
  • leukemic mice spleens weigh 600 to 1,600mg compared to 80 to 150mg in wild-type mice
• spleen hyperplasia (MGI Ref ID J:90331)
  • due to expansion of myeloid cells
• decreased B cell number (MGI Ref ID J:90331)
  • mice have fewer B lymphoid cells
• increased neutrophil cell number (MGI Ref ID J:90331)
  • at 2 to 3 months of age, neutrophil numbers are increased relative to wild-type mice
• liver/biliary system phenotype
• abnormal liver morphology (MGI Ref ID J:90331)
  • abnormal architecture due to expansion of myeloid cells
• increased liver weight (MGI Ref ID J:90331)
  • leukemic mice livers weigh 3.0 to 7.2g compared to 1 to 1.5g in wild-type mice
• liver hyperplasia (MGI Ref ID J:90331)
  • due to expansion of myeloid cells
• cellular phenotype
• abnormal chromosome number (MGI Ref ID J:90331)
  • trisomy 15 is common in mice with T cell lymphomas
• hematopoietic system phenotype
• abnormal hematopoiesis (MGI Ref ID J:90331)
  • moribund mice accumulate immature myeloid cells in bone marrow and spleen
• decreased B cell number (MGI Ref ID J:90331)
  • mice have fewer B lymphoid cells
• increased neutrophil cell number (MGI Ref ID J:90331)
  • at 2 to 3 months of age, neutrophil numbers are increased relative to wild-type mice
• abnormal proerythroblast morphology (MGI Ref ID J:90331)
  • mice have fewer erythroid cells
• abnormal spleen morphology (MGI Ref ID J:90331)
  • abnormal architecture due to expansion of myeloid cells
• enlarged spleen (MGI Ref ID J:90331)
  • spleen is 1.5 to 2 times bigger than in wild-type mice
• increased spleen weight (MGI Ref ID J:90331)
  • leukemic mice spleens weigh 600 to 1,600mg compared to 80 to 150mg in wild-type mice
• spleen hyperplasia (MGI Ref ID J:90331)
  • due to expansion of myeloid cells

View Research Applications

Research Applications

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

Cancer Research
Genes Regulating Growth and Proliferation
Increased Tumor Incidence (Leukemia: lymphatic)
Increased Tumor Incidence (Lymphomas)

Developmental Biology Research
Internal/Organ Defects (Lymphoid Tissue Defects)
Internal/Organ Defects (hematopoietic defects)
Lymphoid Tissue Defects (hematopoietic defects)

Hematological Research
Hematopoietic Defects

Immunology and Inflammation Research
Lymphoid Tissue Defects (hematopoietic development)

Internal/Organ Research
Lymphoid Tissue Defects

Research Tools
Cancer Research (Leukemia)
Cancer Research (tumor immunology)
Hematological Research
Immunology and Inflammation Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Sfpi1tm1.3Dgt
Allele Name		targeted mutation 1.3, Daniel G Tenen
Allele Type		Targeted (knock-out)
Common Name(s)		PU.1 knockdown; UREdelta; UREdelta (neo-);
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl+
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Sfpi1, SFFV proviral integration 1
Chromosome		2
Gene Common Name(s)		Dis-1; OF; PU.1; SPI-1; SPI-A; Sfpi-1; Tcfpu1; Tfpu.1; transcription factor PU.1;
General Note		Although expression of PU.1/SFPI1 in hematopoietic stem cells, myeloid progenitor cells and granulocytes is similar in mice homozygous for this mutation and for Sfpi1tm1.1Dgt ("UREdeltaneo"), which retains the PGK-neo cassette, mice with the present mutation develop acute myelocytic leukemia (AML) with a lower penetrance (29% vs. 97%) and a longer latency (6-12 months vs. 3-8 months) than do those with Sfpi1tm1.1Dgt. Mice with the present mutation often die of T cell lymphoma before the time of onset of AML. ( J:106789; J:90331) The phenotypic difference may be due to genetic background differences, as Sfpi1tm1.1Dgt was analyzed on a ~50% BALB/c and the present mutation on a >50% 129/Sv background.
Molecular Note		This allele was generated from Sfpi1tm1Dgt by sequential deletion of the loxP-flanked 3.4-kb upstream regulatory element (URE), located 14 kb upstream from the endogenous gene, and of the FRT-flanked PGK-Neo cassette residing immediately upstream of the URE, achieved by crossing mice bearing the Sfpi1 mutations with animals ubiquitously expressing Cre and FLP recombinase, respectively. Thus it lacks both the normal URE and the introduced PGK-neo cassette, with single loxP and FRT sites marking their former locations. Expression of the gene in bone marrow and purified hematopoietic stem cells (HSCs) of homozygous mutant mice is reduced to ~80% of wild-type levels. [MGI Ref ID J:106040] [MGI Ref ID J:106789] [MGI Ref ID J:90331]

Genotyping

Genotyping Information

Genotyping Protocols

Sfpi1^tm1.3Dgt, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Rosenbauer F; Owens BM; Yu L; Tumang JR; Steidl U; Kutok JL; Clayton LK; Wagner K; Scheller M; Iwasaki H; Liu C; Hackanson B; Akashi K; Leutz A; Rothstein TL; Plass C; Tenen DG. 2006. Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Nat Genet 38(1):27-37. [PubMed: 16311598]  [MGI Ref ID J:106040]

Additional References

Sfpi1^tm1.3Dgt related

Rosenbauer F; Wagner K; Kutok JL; Iwasaki H; Le Beau MM; Okuno Y; Akashi K; Fiering S; Tenen DG. 2004. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet 36(6):624-30. [PubMed: 15146183]  [MGI Ref ID J:90331]

Steidl U; Rosenbauer F; Verhaak RG; Gu X; Ebralidze A; Otu HH; Klippel S; Steidl C; Bruns I; Costa DB; Wagner K; Aivado M; Kobbe G; Valk PJ; Passegue E; Libermann TA; Delwel R; Tenen DG. 2006. Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells. Nat Genet 38(11):1269-77. [PubMed: 17041602]  [MGI Ref ID J:115331]

Zhang P. 2006. Sfpi1<tm1.3Dgt>(URE-delta [neo-] development Personal Communication :.  [MGI Ref ID J:106789]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as heterozygotes.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Heterozygote from the colony
	Wild-type from the colony
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.

General Terms and Conditions

See Terms of Use

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

Terms of Use

General Terms and Conditions

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

For additional Licensing and Use Restrictions view the link(s) below:
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General inquiries

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fax:	207-288-6655

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