Homozygous (12/15-LO-deficient) mutant mice develop a myeloproliferative disorder (similar to human chronic myelogenous leukemia) that progresses to transplantable leukemia. These mutant mice may be useful in studying myeloproliferative disorders, chronic myelogenous leukemia, and other cancers.
Colin D. Funk, Queen's University
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.
Specifically, Middleton et al. 2006 J Exp Med. 203:2529 reported that Alox15 knock-out mice (from Stock No. 002778) older than 10 weeks of age developed MPD with complete penetrance - 85% grossly asymptomatic (chronic phase) while 15% moribund (crisis phase). They also detected myeloid infiltrates in the skin of moribund Alox15 knock-out mice that correlated with the development of dermatitis.
Furthermore, Kim et al. 2018 Sci Rep. 8:8856 reports that Alox15 knock-out mice (from Stock No. 002778) have increased proinflammatory signaling that results in hair loss in adult mice (average onset of 16 weeks) and disrupted structural integrity of the dorsal skin. Furthermore, Alox15 knock-out results in loss of hair follicle stem cells and abnormal transition of dermal adipocytes into fibroblasts. They report that treatment with resolvin D2 reduced skin inflammation in Alox15 knock-out mice.
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 (see SNP note below).
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, 3 of 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 mixed C57BL/6J ; C57BL/6N genetic background.
|Allele Name||targeted mutation 1, Colin D Funk|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||12/15-LO-; 12/15-LO KO; 12Lox KO; L-12/15-LOX KO; L-12LO-|
|Gene Symbol and Name||Alox15, arachidonate 15-lipoxygenase|
|Strain of Origin||129S2/SvPas|
|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.|
|Mutations Made By|| |
Colin Funk, Queen's University
When maintaining a live colony, homozygous mice can be bred. Coat color expected from breeding is black.
When using the 12/15-LOX KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #002778 in your Materials and Methods section.
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