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).