5.2.1 Nude Mouse
Since the 1970s, athymic nude mice have been widely used for xenotransplantation of human solid tumors(Fogh, Fogh & Orfeo, 1977). Athymic nude mice are mutant mice with congenital thymus defects and lack functional T cells. In 1982, researchers tried for the first time to transplant primary AML cells into nude mice whose Foxn1gene (encoding for a forkhead box transcription factor) mutations caused immune damage. Since the functions of B cells and NK cells were basically normal(Panoutsakopoulou, Little, Sieck, Blankenhorn & Blank, 1998), the transplantation effect of leukemia cells was very poor, only granulocytic sarcoma is produced, and bone marrow and other organs are not affected(Nara & Miyamoto, 1982). In 1992, Federica Cavallo established a leukemia animal model that selectively invaded the CNS. This model reproduces some aspects of human meningeal leukemia, if human leukemia cells diffuse directly into the CNS mainly through the bone marrow, then cranial radiotherapy may be a more effective method to prevent leukemia cell infiltration than systemic blood therapy(Cavallo, Forni, Riccardi, Soleti, Di Pierro & Forni, 1992).
Xenograft nude mouse models all along have played a pivotal role in studying the clinical features, pathogenesis and medication of ALL, which are closer to the clinic because they retain the tumor biological characteristics. A human leukemia xenograft model established by transplanting highly tumorigenic leukemia cell line HL-60 cells subcutaneously in nude mice to investigate the growth inhibition and apoptosis-inducing effects of deferoxamine (DFO) combined with arsenic trioxide (ATO) on human HL-60 nude mice transplanted tumors and its mechanism. The results showed that the drug combination inhibited tumor growth more significantly than the drugs alone, this finding provides solid evidence for adjuvant therapy of leukemia(Yu, Wang, Ren, Zeng & Liu, 2014). Signal transducer and activator of transcription 5(STAT5) is frequently overexpressed or aberrantly activated in leukemia and plays an important role in cell survival, proliferation and differentiation(Verhoeven et al., 2020). On this basis, researchers have discovered that STAT5 can be used as a therapeutic target with the aid of nude mouse transplantation model. STAT5 constitutively activated cell line HL-60CS5 cells were injected into female BALB/c nude mice to establish a xenograft model, and a new AURKA inhibitor AKI604 was found to overcome STAT5-induced leukemic proliferation by inducing mitochondrial damage in AML treatment, suggesting that targeted therapeutic strategies overcome the disadvantages of intolerance and drug resistance of chemotherapy regimens for the treatment of acute leukemia(Wang et al., 2020).
5.2.2 The Severe Combine Immunodeficient (SCID) Mouse
In 1983, Dr. Bosma discovered SCID mice while raising a colony of C.B-17 mice, and the genetic background of SCID is basically the same as that of BALB/c mice. SCID mice are mutant mice caused by mutations in a single recessive gene on autosome 16 of C.B-17 inbred mice. Inactivation and mutation of the protein kinase DNA-activated catalytic polypeptide (Prkdc) gene leads to incorrect recombination of the immunoglobulin V-D-J gene and ultimately leading to the inability of T and B lymphocytes to develop properly(Bosma, Custer & Bosma, 1983).
The development of SCID mice was an important progress for the development of humanized ALL mouse models. SCID mice have less immune rejection to human tumor cells, and the implantation rate of primary ALL cells by intraperitoneal injection or implanted under the kidney capsules is significantly increased(Sawyers, Gishizky, Quan, Golde & Witte, 1992). Later, researchers treated SCID mice with human stem cell factor (SCF) and granulocyte-macrophage colony stimulating factor (GM-CSF). This was the first evidence of a hierarchy of leukemia cells. This model replicates many aspects of human leukemia and defines a new type of leukemia-initiating cell that is less mature than colony-forming cells(Lapidot et al., 1994). In1995, the first adult ALL SCID mouse leukemia model was established successfully, describing for the first time the relationship between the phenotypic-genotypic characteristics of adult ALL cells and their implantation and propagation in SCID animals, providing an in vivo adult ALL model to study the biology and pathophysiology of adult ALL and therapeutic methods(Jeha et al., 1995). In addition, the SCID mouse model is also used to evaluate the advantages and prospects of targeted therapy.CD19-targeted therapy is a novel cell therapy with significant efficacy and is considered one of the most promising oncology treatments for acute leukemia and non-Hodgkin’s lymphoma. Researchers established the first SCID mouse model which using monoclonal antibodies targeted therapy to treat ALL. They demonstrated that when the radioactive metal binds to the anti-CD19 antibody, it can specifically target the spleen, liver and bone marrow infiltrated by leukemia cells, prolonging the survival time of SCID mice(Mitchell et al., 2003). This model can be used to evaluate treatment methods and lay the foundation for subsequent targeted drug research.
Notably, approximately 10% of SCID mice show ”leakiness” of the SCID mutation in youth(Forsberg et al., 2019; Nonoyama, Smith, Bernstein & Ochs, 1993), that is, a certain degree of immune function recovery, which is manifested in the recovery of functional B and T cell activity, the enhancement of NK cell activity, and the activation of complement which reduces the implantation efficiency(Carroll, Hardy & Bosma, 1989).