NKG-SGM3/hIL6/Kit*V831M Mice

Catalog Number: C001695

Strain Name: NOD.Cg-PrkdcscidIl2rgem1Kitem2(V831M)Il6em1(hIL6)Gt(ROSA)26Sorem1(hIL3-P2A-hCSF2-T2A-hKITLG)/Cya

Genetic Background: NKG

Reproduction: Homozygote NKG-Kit*V831M mice x Heterozygote NKG-SGM3 mice x Homozygote NKG-hIL6 mice

 

Strain Description

NKG mice are a type of severe immunodeficient mouse developed by Cyagen by deleting the Il2rg gene from the NOD-Scid strain. This strain lacks mature T, B, and NK cells, has reduced complement activity, and weak macrophage phagocytosis of human cells. As a result, NKG mice can efficiently engraft human hematopoietic stem cells (HSC), peripheral blood mononuclear cells (PBMC), patient-derived xenografts (PDX), or adult stem cells and tissues.

Interleukin-6 (IL-6) is a cytokine that plays a crucial role in inflammation and B cell maturation. It is primarily produced and secreted into the bloodstream at acute and chronic inflammatory sites. IL-6 induces transcriptional inflammatory responses through its receptor, IL6Rα. Research indicates that immunodeficient mice carrying the human IL6 gene effectively enhance the differentiation of human monocytes and macrophages during HSC reconstruction [1].

The KIT gene encodes a receptor tyrosine kinase (c-Kit or CD117) that is activated by its ligand, stem cell factor (SCF). Activation of this receptor triggers phosphorylation of a variety of downstream intracellular proteins, governing essential cellular processes such as proliferation, differentiation, migration, and apoptosis across numerous cell types. The KIT gene plays a pivotal role in hematopoiesis, stem cell maintenance, gametogenesis, melanogenesis, and the development and function of mast cells. Mutations in KIT are implicated in a range of pathologies, including gastrointestinal stromal tumors, mastocytosis, and acute myeloid leukemia. Importantly, immunodeficient mice harboring the KIT W41 mutation (V831M) have demonstrated the ability to undergo human HSC transplantation without the need for irradiation, while maintaining high rates of engraftment [2-3].

The SCF gene, also known as KITLG, encodes the receptor-type protein-tyrosine kinase KIT ligand. This gene is crucial for the development of germ cells and neurons during embryogenesis and plays a significant role in hematopoiesis. The GM-CSF gene, or CSF2, encodes a cytokine that orchestrates the production, differentiation, and function of granulocytes and macrophages. Meanwhile, the IL3 gene encodes a growth-promoting cytokine essential for the proliferation of various blood cell types, influencing cell growth, differentiation, and apoptosis. Research demonstrates that severe immunodeficient mice expressing human IL3, GM-CSF (CSF2), and SCF (KITLG) show markedly enhanced engraftment efficiency in the xenotransplantation of acute myeloid leukemia (AML) [4], supporting stable engraftment of myeloid lineages and regulatory T cell populations [5].

NKG-SGM3/hIL6/Kit*V831M mice are mouse models obtained by mating KIT W41 mutation (V831M) mouse models (Catalog Number: I001175) with IL6 humanized mouse models (Catalog Number: I001176) and IL3, KITLG and CSF2 triple humanized mouse models (Catalog Number: I001177). These mice express human IL6, IL3, KITLG, and CSF2 genomic sequences, as well as mouse KIT genomic sequences carrying the W41 mutation (V831M). This model is a valuable tool for immuno-oncology, immunology, and infectious disease research.

 

Strain Strategy

  • Gene Editing Strategy for NKG-Kit*V831M Mice. The p.V831M (GTG to ATG) mutation is introduced into the mouse Kit gene through gene editing technology.



  • Gene editing strategy of NKG-hIL6 mice. The sequences from ATG start codon to TAG stop codon of the endogenous mouse Il6 gene will be replaced with the sequences from ATG start codon to TAG stop codon of the human IL6 gene.



  • Gene editing strategy of NKG-SGM3 mice. For the Kl model, the "SV40 promoter-Kozak-Human IL3 CDS-P2A-Human CSF2 CDS-T2A-Human KITLG CDS-rBG PA" cassette will be cloned into intron 1 of ROSA26.



Application

  • Construction of humanized mouse models for the immune system;
  • Studies on the human immune and hematopoietic systems;
  • Xenotransplantation of human cell lines (CDX) for drug screening and efficacy evaluation;
  • Xenotransplantation of patient-derived tumor tissues (PDX) for drug screening and efficacy evaluation;

 

References
[1]Hanazawa A, Ito R, Katano I, Kawai K, Goto M, Suemizu H, Kawakami Y, Ito M, Takahashi T. Generation of Human Immunosuppressive Myeloid Cell Populations in Human Interleukin-6 Transgenic NOG Mice. Front Immunol. 2018 Feb 2;9:152.
[2]McIntosh BE, Brown ME, Duffin BM, Maufort JP, Vereide DT, Slukvin II, Thomson JA. Nonirradiated NOD,B6.SCID Il2rγ-/- Kit(W41/W41) (NBSGW) mice support multilineage engraftment of human hematopoietic cells. Stem Cell Reports. 2015 Feb 10;4(2):171-80.
[3]Cosgun KN, Rahmig S, Mende N, Reinke S, Hauber I, Schäfer C, Petzold A, Weisbach H, Heidkamp G, Purbojo A, Cesnjevar R, Platz A, Bornhäuser M, Schmitz M, Dudziak D, Hauber J, Kirberg J, Waskow C. Kit regulates HSC engraftment across the human-mouse species barrier. Cell Stem Cell. 2014 Aug 7;15(2):227-38.
[4]Wunderlich M, Chou FS, Link KA, Mizukawa B, Perry RL, Carroll M, Mulloy JC. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia. 2010 Oct;24(10):1785-8.
[5]Billerbeck E, Barry WT, Mu K, Dorner M, Rice CM, Ploss A. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rγ(null) humanized mice. Blood. 2011 Mar 17;117(11):3076-86.