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 Homozygote x Homozygote         (Female x Male) Species laboratory mouse Background Strain C57BL/6 Donor Strain 129S2 via D3-H ES cell line Generation N11F?+F23 (30-DEC-08)

Description
Homozygous (12/15-LO-deficient) mutant mice are viable and fertile. 12/15-LO-deficient mice develop a myeloproliferative disorder (MPD) (similar to human chronic myelogenous leukemia (CML)) that progresses to transplantable leukemia. Chronic MPD stage homozygotes exhibit increased activation of the phosphatidylinositol 3–kinase (PI3-K) pathway, hyperphosphorylation/decreased nuclear accumulation of the transcription factor interferon consensus sequence binding protein (ICSBP), and increased expression of the oncoprotein Bcl-2; all of which are reversible upon treatment with a PI3-K inhibitor. The evolution of MPD to leukemia is associated with additional regulation of ICSBP at the RNA level. Peritoneal macrophages have altered arachidonic acid metabolism as well as a diminished ability to oxidize low density lipoprotein (LDL) following stimulation. These mutant mice may be useful in studying myeloproliferative disorders, chronic myelogenous leukemia, and other cancers.

Development
Neomycin resistance cassettes were inserted into exon 3. Original background was C57BL/6 x 129Sv. As of April 2007, live mice have been backcrossed to C57BL/6J for 11 generations.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Alox15^tm1Fun/Alox15^tm1Fun

        B6.129S2-Alox15^tm1Fun/J

• hematopoietic system phenotype
• abnormal bone marrow cell number (MGI Ref ID J:119405)
  • increase in number of myeloid cells and progenitors, as well as megkaryocytes
• abnormal myeloblast morphology/development (MGI Ref ID J:119405)
  • at death, cells in bone marrow of homozygous mice consist of greater than 25% myeloblasts
• increased basophil cell number (MGI Ref ID J:119405)
  • basophilia observed in asymptomatic and moribund mice
• abnormal myelopoiesis (MGI Ref ID J:119405)
  • increase in numbers of myeloid cells in bone marrow, spleen, blood and lymph nodes as compared to control
  • cell cycle analysis indicates an increase in proliferative capacity of splenic myeloid cells and a decrease in the percentage of apoptotic cells
• abnormal spleen red pulp morphology (MGI Ref ID J:119405)
  • disrupted compartmentalization of red pulp
• intermingled spleen red and white pulp (MGI Ref ID J:119405)
  • moribund mice exhibit complete loss of splenic compartmentalization
• abnormal spleen white pulp morphology (MGI Ref ID J:119405)
  • disrupted compartmentalization of white pulp
• abnormal spleen B cell follicle morphology (MGI Ref ID J:119405)
  • decrease in number of follicles
• intermingled spleen red and white pulp (MGI Ref ID J:119405)
  • moribund mice exhibit complete loss of splenic compartmentalization
• anemia (MGI Ref ID J:119405)
  • presumed cause of premature death
• increased leukocyte cell number (MGI Ref ID J:119405)
  • blood leukocystosis observed in asymptomatic and moribund mice
• increased basophil cell number (MGI Ref ID J:119405)
  • basophilia observed in asymptomatic and moribund mice
• increased spleen weight (MGI Ref ID J:119405)
  • progressive splenomegaly is observed after 8 weeks of age
• immune system phenotype
• abnormal lymph node morphology (MGI Ref ID J:119405)
  • although not enlarged, lymph nodes exhibit progressive hypercellularity
  • pseudo-Gaucher cells observed in lymph nodes
  • increase in GR-1+ myeloid cells as compared to controls
• abnormal myelopoiesis (MGI Ref ID J:119405)
  • increase in numbers of myeloid cells in bone marrow, spleen, blood and lymph nodes as compared to control
  • cell cycle analysis indicates an increase in proliferative capacity of splenic myeloid cells and a decrease in the percentage of apoptotic cells
• abnormal spleen red pulp morphology (MGI Ref ID J:119405)
  • disrupted compartmentalization of red pulp
• intermingled spleen red and white pulp (MGI Ref ID J:119405)
  • moribund mice exhibit complete loss of splenic compartmentalization
• abnormal spleen white pulp morphology (MGI Ref ID J:119405)
  • disrupted compartmentalization of white pulp
• abnormal spleen B cell follicle morphology (MGI Ref ID J:119405)
  • decrease in number of follicles
• intermingled spleen red and white pulp (MGI Ref ID J:119405)
  • moribund mice exhibit complete loss of splenic compartmentalization
• dermatitis (MGI Ref ID J:119405)
  • myeloid infiltrates observed in skin of moribund mice
• increased leukocyte cell number (MGI Ref ID J:119405)
  • blood leukocystosis observed in asymptomatic and moribund mice
• increased basophil cell number (MGI Ref ID J:119405)
  • basophilia observed in asymptomatic and moribund mice
• increased spleen weight (MGI Ref ID J:119405)
  • progressive splenomegaly is observed after 8 weeks of age
• life span-post-weaning/aging
• premature death (MGI Ref ID J:119405)
  • increase in death rate of homozygous mice as compared to controls
  • 80% survival at 12 months of age
  • severe anemia is most likely cause of death
• tumorigenesis
• chronic myelocytic leukemia (MGI Ref ID J:119405)
  • mice older than 10 weeks develop a malignant myeloproliferative disease at 100% penetrance that can progress to transplantable leukemia
• skin/coat/nails phenotype
• dermatitis (MGI Ref ID J:119405)
  • myeloid infiltrates observed in skin of moribund mice

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

Alox15^tm1Fun/Alox15^tm1Fun

        involves: 129/Sv * C57BL/6

• endocrine/exocrine gland phenotype
• *normal* endocrine/exocrine gland phenotype (MGI Ref ID J:44778)
  • no defect detected in pituitary gland, adrenals, and pancreas
• hematopoietic system phenotype
• *normal* hematopoietic system phenotype (MGI Ref ID J:44778)
  • mutants had normal total blood cell counts, normal leukocyte differentials, normal reticulocyte numbers, normal hemoglobin values, and normal hematocrit values
• immune system phenotype
• abnormal immune system physiology (MGI Ref ID J:44778)
  • altered arachadonic acid metabolism in peritoneal macrophages upon calcium ionophore stimulation: undetectable 12-hydroxyeicosatetraenoic acid (12-HETE), trace amounts of 15-hydroxyeicosatetraenoic acid (15-HETE), increased concentrations of 5-hydroxyeicosatetraenoic acid (5-HETE), however no defect detected in the spleen
• reproductive system phenotype
• *normal* reproductive system phenotype (MGI Ref ID J:44778)
  • mutants were fertile

View Research Applications

Research Applications

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

Alox15^tm1Fun related

Cardiovascular Research
Atherosclerosis
Vascular Defects (defective macrophage function)

Immunology and Inflammation Research
Inflammation

Research Tools
Cancer Research (Leukemia)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Alox15tm1Fun
Allele Name		targeted mutation 1, Colin Funk
Allele Type		Targeted (knock-out)
Common Name(s)		12/15-LO KO; 12/15-LO-; L-12/15-LOX KO; L-12LO-;
Mutation Made By		Colin Funk,   University of Pennsylvania
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3H
ES Cell Line Strain		129S2/SvPas
Gene Symbol and Name		Alox15, arachidonate 15-lipoxygenase
Chromosome		11
Gene Common Name(s)		12-LO; 12-LOX; 15-LOX-1; 15-LOX2; Alox12; Alox12l; L-12LO; arachidonate 12-lipoxygenase, leukocyte;
Molecular Note		Insertion of a neomycin resistance cassette into exon 3 disrupted the Alox15 gene. Northern blot analyses of resident peritoneal macrophages and of bone marrow-derived macrophages did not detect transcript in homozygous mutant mice. Western blot analysis of resident peritoneal macrophages did not detect ALOX15 in homozygous mutant mice. [MGI Ref ID J:44778]

Genotyping

Genotyping Information

Genotyping Protocols

Alox15^tm1Fun, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Middleton MK; Zukas AM; Rubinstein T; Jacob M; Zhu P; Zhao L; Blair I; Pure E. 2006. Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease. J Exp Med 203(11):2529-40. [PubMed: 17043146]  [MGI Ref ID J:119405]

Sun D; Funk CD. 1996. Disruption of 12/15-lipoxygenase expression in peritoneal macrophages. Enhanced utilization of the 5-lipoxygenase pathway and diminished oxidation of low density lipoprotein. J Biol Chem 271(39):24055-62. [PubMed: 8798642]  [MGI Ref ID J:44778]

Additional References

Emerson MR; LeVine SM. 2004. Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase. Brain Res 1021(1):140-5. [PubMed: 15328042]  [MGI Ref ID J:92011]

Klein RF; Allard J; Avnur Z; Nikolcheva T; Rotstein D; Carlos AS; Shea M; Waters RV; Belknap JK; Peltz G; Orwoll ES. 2004. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 303(5655):229-32. [PubMed: 14716014]  [MGI Ref ID J:87403]

Zhao L; Cuff CA; Moss E; Wille U; Cyrus T; Klein EA; Pratico D; Rader DJ; Hunter CA; Pure E; Funk CD. 2002. Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia. J Biol Chem 277(38):35350-6. [PubMed: 12122008]  [MGI Ref ID J:79120]

Alox15^tm1Fun related

Anning PB; Coles B; Bermudez-Fajardo A; Martin PE; Levison BS; Hazen SL; Funk CD; Kuhn H; O'donnell VB. 2005. Elevated endothelial nitric oxide bioactivity and resistance to Angiotensin-dependent hypertension in 12/15-lipoxygenase knockout mice. Am J Pathol 166(3):653-62. [PubMed: 15743778]  [MGI Ref ID J:96724]

Chinnici CM; Yao Y; Ding T; Funk CD; Pratico D. 2005. Absence of 12/15 lipoxygenase reduces brain oxidative stress in apolipoprotein e-deficient mice. Am J Pathol 167(5):1371-7. [PubMed: 16251421]  [MGI Ref ID J:102399]

Cyrus T; Pratico D; Zhao L; Witztum JL; Rader DJ; Rokach J; FitzGerald GA; Funk CD. 2001. Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice. Circulation 103(18):2277-82. [PubMed: 11342477]  [MGI Ref ID J:103392]

Cyrus T; Witztum JL; Rader DJ; Tangirala R; Fazio S; Linton MF; Funk CD. 1999. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice [see comments] J Clin Invest 103(11):1597-604. [PubMed: 10359569]  [MGI Ref ID J:55714]

Dioszeghy V; Rosas M; Maskrey BH; Colmont C; Topley N; Chaitidis P; Kuhn H; Jones SA; Taylor PR; O'Donnell VB. 2008. 12/15-Lipoxygenase regulates the inflammatory response to bacterial products in vivo. J Immunol 181(9):6514-24. [PubMed: 18941242]  [MGI Ref ID J:140717]

Emerson MR; LeVine SM. 2004. Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase. Brain Res 1021(1):140-5. [PubMed: 15328042]  [MGI Ref ID J:92011]

Feinmark SJ; Begum R; Tsvetkov E; Goussakov I; Funk CD; Siegelbaum SA; Bolshakov VY. 2003. 12-lipoxygenase metabolites of arachidonic acid mediate metabotropic glutamate receptor-dependent long-term depression at hippocampal CA3-CA1 synapses. J Neurosci 23(36):11427-35. [PubMed: 14673007]  [MGI Ref ID J:86891]

George J; Afek A; Shaish A; Levkovitz H; Bloom N; Cyrus T; Zhao L; Funk CD; Sigal E; Harats D. 2001. 12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice. Circulation 104(14):1646-50. [PubMed: 11581143]  [MGI Ref ID J:86385]

Gronert K; Maheshwari N; Khan N; Hassan IR; Dunn M; Laniado Schwartzman M. 2005. A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense. J Biol Chem 280(15):15267-78. [PubMed: 15708862]  [MGI Ref ID J:98733]

Klein RF; Allard J; Avnur Z; Nikolcheva T; Rotstein D; Carlos AS; Shea M; Waters RV; Belknap JK; Peltz G; Orwoll ES. 2004. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 303(5655):229-32. [PubMed: 14716014]  [MGI Ref ID J:87403]

Li Q; Cheon YP; Kannan A; Shanker S; Bagchi IC; Bagchi MK. 2004. A novel pathway involving progesterone receptor, 12/15-lipoxygenase-derived eicosanoids, and peroxisome proliferator-activated receptor gamma regulates implantation in mice. J Biol Chem 279(12):11570-81. [PubMed: 14688261]  [MGI Ref ID J:88738]

McDuffie M; Maybee NA; Keller SR; Stevens BK; Garmey JC; Morris MA; Kropf E; Rival C; Ma K; Carter JD; Tersey SA; Nunemaker CS; Nadler JL. 2008. Nonobese diabetic (NOD) mice congenic for a targeted deletion of 12/15-lipoxygenase are protected from autoimmune diabetes. Diabetes 57(1):199-208. [PubMed: 17940120]  [MGI Ref ID J:132435]

Middleton MK; Rubinstein T; Pure E. 2006. Cellular and molecular mechanisms of the selective regulation of IL-12 production by 12/15-lipoxygenase. J Immunol 176(1):265-74. [PubMed: 16365418]  [MGI Ref ID J:126265]

Paintlia AS; Paintlia MK; Singh I; Singh AK. 2006. IL-4-induced peroxisome proliferator-activated receptor gamma activation inhibits NF-kappaB trans activation in central nervous system (CNS) glial cells and protects oligodendrocyte progenitors under neuroinflammatory disease conditions: implication for CNS-demyelinating diseases. J Immunol 176(7):4385-98. [PubMed: 16547277]  [MGI Ref ID J:129865]

Reddy MA; Kim YS; Lanting L; Natarajan R. 2003. Reduced growth factor responses in vascular smooth muscle cells derived from 12/15-lipoxygenase-deficient mice. Hypertension 41(6):1294-300. [PubMed: 12707289]  [MGI Ref ID J:103032]

Seiler A; Schneider M; Forster H; Roth S; Wirth EK; Culmsee C; Plesnila N; Kremmer E; Radmark O; Wurst W; Bornkamm GW; Schweizer U; Conrad M. 2008. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab 8(3):237-48. [PubMed: 18762024]  [MGI Ref ID J:139668]

Taylor AM; Hanchett R; Natarajan R; Hedrick CC; Forrest S; Nadler JL; McNamara CA. 2005. The effects of leukocyte-type 12/15-lipoxygenase on Id3-mediated vascular smooth muscle cell growth. Arterioscler Thromb Vasc Biol 25(10):2069-74. [PubMed: 16037566]  [MGI Ref ID J:135379]

Walters CL; Wang BC; Godfrey M; Sun D; Funk CD; Blendy JA. 2003. Augmented responses to morphine and cocaine in mice with a 12-lipoxygenase gene disruption. Psychopharmacology (Berl) 170(2):124-31. [PubMed: 12845410]  [MGI Ref ID J:103877]

Wen Y; Gu J; Vandenhoff GE; Liu X; Nadler JL. 2008. Role of 12/15-lipoxygenase in the expression of MCP-1 in mouse macrophages. Am J Physiol Heart Circ Physiol 294(4):H1933-8. [PubMed: 18296557]  [MGI Ref ID J:135665]

Zhao L; Cuff CA; Moss E; Wille U; Cyrus T; Klein EA; Pratico D; Rader DJ; Hunter CA; Pure E; Funk CD. 2002. Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia. J Biol Chem 277(38):35350-6. [PubMed: 12122008]  [MGI Ref ID J:79120]

Zhao L; Pratico D; Rader DJ; Funk CD. 2005. 12/15-Lipoxygenase gene disruption and vitamin E administration diminish atherosclerosis and oxidative stress in apolipoprotein E deficient mice through a final common pathway. Prostaglandins Other Lipid Mediat 78(1-4):185-93. [PubMed: 16303615]  [MGI Ref ID J:112785]

van Leyen K; Kim HY; Lee SR; Jin G; Arai K; Lo EH. 2006. Baicalein and 12/15-lipoxygenase in the ischemic brain. Stroke 37(12):3014-8. [PubMed: 17053180]  [MGI Ref ID J:135968]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice can be bred. Coat color expected from breeding is black.
Mating System	Homozygote x Homozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. 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
	000664 C57BL/6J
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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Ordering and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
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Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.