NKG-Kit*V831M Mouse

NKG mice are a type of severe immunodeficient mouse developed by Cyagen by knocking out the Il2rg gene in the NOD-Scid background strain. This strain lacks mature T, B, and NK immune cells, has reduced complement activity, and weak phagocytic activity of macrophages against human cells. Therefore, 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.

Significant physiological and immunological differences exist between humans and mice in immunological research, making direct extrapolation of murine data to humans challenging. However, by transplanting human PBMCs or HSCs into immunodeficient mice, human immune components can partially or fully replace the murine immune system, creating an in vivo model that facilitates the study of human immune functions. Typically, successful reconstitution of HSCs in severely immunodeficient mice requires myeloablative irradiation to deplete endogenous murine HSCs. This process creates a niche for human HSC engraftment while reducing the risk of host immune rejection. Nevertheless, myeloablative irradiation is associated with off-target damage to various tissues and organs, impacting the survival and functional integrity of engrafted cells ^[1-2]. Thus, genetic modification of murine HSC function to obviate the need for irradiation during HSC reconstitution represents a significant advancement in improving post-reconstitution survival and overall health of the mice.

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 ^[3-4]. The NKG-Kit*V831M mouse strain is generated by introducing the W41 mutation (V831M) into the KIT gene of the NKG mouse. Compared to standard NKG mice, these mice eliminate the need for irradiation during HSC reconstitution, thereby avoiding the deleterious effects of irradiation on the hematopoietic, gastrointestinal, and nervous systems. This feature renders NKG-Kit*V831M mice an invaluable tool for developing and evaluating tumor immunotherapies and conducting drug efficacy assessments.