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\begin{document}

\title{Animal Models of Acute lymphoblastic leukemia: recapitulating the human
disease to evaluate drug efficacy and discover therapeutic targets}



\author[1]{Qianling Xin}%
\author[1]{Zhaoying Chen}%
\author[1]{Wei Wei}%
\author[1]{Yu-Jing Wu}%
\affil[1]{Anhui Medical University}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Acute lymphoblastic leukemia (ALL) is a malignant hematologic tumor with
highly aggressive characteristics, which has few clinically effective
drugs. It is meaningful to gain a better understanding of its
pathogenesis in order to discover and evaluate potential therapeutic
drugs and new treatment targets. However, the process of new drugs from
research and development to clinical application is long and difficult.
Many promising drugs were rejected by the US Food and Drug
Administration (FDA) due to serious adverse drug reactions (ADR) in
clinical phase I trials. Animal models provide us with an excellent tool
to understand the complex pathological mechanisms of human diseases, to
evaluate the potential of new targeted drugs and to assess the potential
ADR they may have on healthy organs. In this article we briefly
introduce the clinical status of ALL, review ALL animal models'
progression, their roles in revealing the pathogenesis of ALL and drug
development.%
\end{abstract}%



\sloppy


\textbf{1.Introduction}

ALL is a serious hematological system disease with highly aggressive
characteristics(Terwilliger \& Abdul-Hay, 2017). The lymphocytes
proliferate and accumulate abnormally in the bone marrow, and transfer
to other tissues and organs, causing systemic organs and tissue
infiltrations and infections, seriously affecting normal hematopoietic
function(Tan, Bertulfo \& Sanda, 2017). ALL includes T-cell acute
lymphoblastic leukemia (T-ALL) and B-cell acute lymphoblastic leukemia
(B-ALL). Among them, T-ALL accounts for about 12\% to 15\% in pediatric
ALL cases (You, Medeiros \& Hsi, 2015). ALL is prone to occur in
adolescents and children, and patients under 20 years old account for
60\% of the total cases. The five-year event-free survival (EFS) of ALL
is 60\%-75\%(den Hoed et al., 2015), significantly lower than other
types of leukemia. With the development of new drugs and the application
of new technologies, the survival rate of ALL patients has improved. In
pediatric ALL, overall cure rates are approaching 90\%,but in adult
ALL, long-term survival rates are \textasciitilde{} 35 - 50\%(Wei \&
Cleary, 2014), EFS and overall survival (OS) are still less than 70\%,
and the prognosis of relapsed and refractory ALL is
poor(S\selectlanguage{ngerman}ánchez-Martínez et al., 2019). Due to ethical reasons, clinically
common refractory diseases are obviously impossible to replicate in
human body to study the pathological and genetic mechanisms of disease
occurrence(Adams et al., 1985). The remarkable functions of animal
models are to: (1) simulate human genetic conditions and tumor growth
microenvironment, (2) evaluate drug treatment effects, targets and ADR,
(3) assess biomarkers related to tumor malignant transformation, (4)
study the exogenous predisposing factors and pathogenesis of leukemia.
At present, the animals commonly used to study ALL are mainly including
mice, rats, zebrafish and\emph{Drosophila melanogaster} (Milne, 2017).
Among them, mice are very similar to humans in terms of genetics and
hematopoietic system, and this unique advantage makes it important to
establish mouse leukemia models to study the cellular molecular biology,
biochemical and immunological characteristics, pathophysiological
changes, pathogenesis, and drug treatment of human leukemia(Fortier \&
Graubert, 2010). Moreover, mice have the advantages of low price and
good reproducibility, and the mouse xenotransplantation model and
transgenic mouse model have been paid more and more attention and
application. This article reviews the latest research progress of animal
models of ALL.

\textbf{2.The Development of Drugs and Treatments of ALL in Recent
Years}

ALL is prone to occur in children around 5 years old and adults around
50 years old, it is mainly considered to be a kind of pediatric
leukemia, accounting for 80\% of cases in children and 20\% in
adults(Jabbour, O'Brien, Konopleva \& Kantarjian, 2015). The 5-year OS
rate for children is about 90\%, compared to only 30\% to 40\% for
adults and elderly patients(Inaba \& Mullighan, 2020). The
chemotherapeutics used in clinical to treat ALL include glucocorticoids,
microtubule inhibitors, anthracyclines, purine and folate
antimetabolites, asparaginase and DNA alkylating agents. In recent
years, great progress has been made in therapeutic target discovery and
drug development, such as antibody-drug conjugate (ADC) inotuzumab
ozogamicin. Inotuzumab ozogamicin is used to treat relapsed or
refractory CD22-positive precursor B-cell ALL (pre-B ALL), and
calaspargase pegol-mknl (Cal-PEG), the asparagine-specific enzyme, is
used to treat children and adolescents ALL. It is worth mentioning that
blinatumomab, which was approved by the FDA in 2014, is the world's
first approved CD19 drug by the FDA for the treatment of Ph-
relapsed/refractory pre-BALL. At present, the main clinical methods to
treat ALL include early intensive therapy, hematopoietic stem cell
transplantation (HSCT), cranial radiation therapy (CRT), Central Nervous
System (CNS)-directed chemotherapy, and chimeric antigen receptor
T-cells (CAR-T). Intensive therapy has significantly improved the
prognosis of pediatric patients, but has the disadvantage of long-term
sequelae. In addition, only 30-40\% of adult ALL patients achieve
long-term remission(Jabbour, O'Brien, Konopleva \& Kantarjian, 2015),
elderly patients and patients with high-risk subtypes of leukemia, such
as early T-cell precursor ALL(ETP-ALL), often cannot tolerate such
treatment regimens and have a poorer prognosis(Ballesteros-Arias, Silva,
Paiva, Carbonetto, Faísca \& Martins, 2019). Although multi-drug
chemotherapy has certain therapeutic advantages, many patients still
relapse and develop refractory leukemia(Gianfelici et al., 2016), and
only 20\% of relapsed pediatric patients can be cured(Richter-Pecha\selectlanguage{polish}ń\selectlanguage{english}ska
et al., 2017). In addition, the use of genotoxic drugs in the treatment
process may lead to secondary malignancies(Teepen et al., 2017). Thus,
we need more effective and less toxic treatments to improve the
prognosis of ALL patients. One report replaced chemotherapy with
targeted therapy, dasatinib combined with dexamethasone to treat ALL,
and then performed two cycles of bispecific anti-CD3 and anti-CD19
antibody blinatumomab, proving that targeted therapy can avoid the
induction of combined chemotherapy, with an OS of 95\% and a
disease-free survival of 88\%(Fo\selectlanguage{ngerman}à et al., 2020). Targeted drugs can
pinpoint and identify cunning tumor cells, delivering precise and
thorough strikes with few ADR cases, without damaging their own tissues.
However, targeted drugs are expensive and mostly are not suitable for
all cancer patients. Animal models can replicate human diseases in a
short period of time, which makes it more convenient and effective to
understand the occurrence and development of human diseases and offers
the measures to prevent and overcome diseases, therefore laying the
foundation to develop potential targeted drugs, individualized treatment
and new therapeutic tools.

\textbf{3.} \textbf{Spontaneous ALL Animal Models}

Some strains of mice will spontaneously develop leukemia during growth,
and only need to screen them to obtain the desired animal model. AKR
mice are the strain with the highest incidence of leukemia, and C57BL
mice can also be used for screening. AKR strains have a high incidence
of lymphocytic leukemia, with a prevalence of 70\%-90\%, and were
commonly used for lymphocytic leukemia research before the development
of transgenic technology and xenograft models. As early as 1975,
researchers studied whether the genetic factors of AKR mouse strain
played a role in the occurrence of leukemia. Later, researchers studied
the sequence characteristics of AKR mouse leukemia virus substrain and
the structure of the integrated recombinant genome in tumor tissues and
found that AKR, as a spontaneous leukemia mouse, was born with a
carcinogenic RNA virus(Quint, Quax, van der Putten \& Berns, 1981).
Compared with tumors induced by experimental methods, the clinical
symptoms of spontaneous models and human tumors are more similar, and
the conditions for tumor occurrence are more natural. However, the
etiology of spontaneous models is quite different from the pathogenesis
of human diseases, which are mainly caused by genetic factors. Moreover,
such model is easily affected by environmental factors, and the model
takes a long time to establish and has poor stability, so it is rarely
used in practice. In order to establish an animal model with a short
incubation period and the tumor that is more similar to human cancer in
pathogenesis, researchers have explored induced animal models.

\textbf{4.Induced ALL Animal Models}

\textbf{4.1 Chemical-Induced ALL Animal Models}

Early work in murine models was based on the chemical-induced models to
test possible therapeutic agents. In 1954, Dr. Law exposed DBA/2 mice to
the carcinogen 3-methylcholantrene and isolated the L1210 leukemia cell
line(Law, Taormina \& Boyle, 1954). The cells can be propagated \emph{in
vitro} , and then injected into a large number of recipients, these
recipients will then develop leukemia. In addition to the important
L1210 cell line, there are several other chemically induced leukemia
cell lines, including P388, P1534 and L5178Y(McCormack, Bruserud \&
Gjertsen, 2005). The use of antimetabolites was first tested in these
models. The animal models established by the transplantation of L1210
and P388 cell lines provide a platform for the test, kinetic study and
evaluation of the anti-leukemia efficacy of chemotherapy drugs(Skipper
\& Perry, 1970), mainly for screening anthracyclines(Casazza, Pratesi,
Giuliani \& Di Marco, 1980), antimetabolites including cytarabine(Kline,
Venditti, Tyrer, Mantel \& Goldin, 1966), and evaluating the efficacy of
topoisomerase II inhibitors(Jensen et al., 1990). In addition to the
transplantation of leukemia cell lines, in the early years, scientists
induced leukemia models by directly administering chemical carcinogens
to laboratory animals. In 1973, researchers repeatedly injected
7,12-dimethylbenzanthracene (DMBA) intravenously on the Wistar/H-Onc rat
strain. After 5-9 months, 10\% of the rats developed leukemia(Gál,
Somfai \& Szentirmay, 1973). In order to explore the genetic damage
caused by benzene-induced acute leukemia, chronically exposed CBA/Ca
mice to 300 ppm benzene by inhalation, and successfully established an
acute leukemia mouse model(Rithidech, Dunn, Bond, Gordon \& Cronkite,
1999). However, these models have some disadvantages which limit their
application. The etiology of chemically induced leukemia is different
from the pathogenesis of most human ALL, because only a minority number
of patients develop leukemia after prolonged exposure to chemical
agents. In addition, this type of model is not stable enough, often
induces multi-site tumors, and has a high fatality rate, so it is rarely
used as a screening model for drugs.

\textbf{4.2 Radiation-InducedALL Animal Models}

Leukemia is one of the first malignant tumors to be identified as
radiation-induced. Many X-ray workers who work near particle
accelerators and ionizing radiation(IR) have developed
leukemia(Committee on the Analysis of Cancer Risks in Populations near
Nuclear Facilities-Phase, Nuclear, Radiation Studies, Division on, Life
\& National Research, 2012). In a systematic study of Japanese atomic
bomb survivors, researchers discovered many patients suffering from
hematological malignancies, especially ALL and AML(Rivina, Davoren \&
Schiestl, 2014). Patients receiving high doses of therapeutic radiation
also often develop leukemia, proving the correlation between radiation
exposure and leukemia. Later, researchers found that IR-induced leukemia
has age differences, with children between the ages of 5 and 9 appearing
to be more likely to develop ALL, while older children and adults are
more likely to develop AML(Little, Weiss, Boice, Darby, Day \& Muirhead,
1999; Preston et al., 1994; Weiss, Darby, Fearn \& Doll, 1995).

Stage I and II lymphoid tumors are mainly treated with radiotherapy,
which uses radiation to kill tumor cells, but often has greater ADR
incidence, damaging its own normal cells and tissues, producing bone
marrow suppression and CNS toxicity. There is a lack of ``perfect''
drugs on the market to reduce radiation-induced toxicity and avoid other
cancerous risks caused by radiation. Animal models are needed to
simulate the molecular and pathophysiological characteristics of human
radiation-induced malignant tumors. The radiation-induced mouse models
are widely used to study the development of radiation-induced leukemia
and gain insights into the biology of human leukemia/lymphoma. For
example, in order to identify the key carcinogenic drivers of
radiation-induced leukemia, researchers administered 1.8 Gy total-body
irradiation(TBI) to mice for four consecutive weeks and performed
whole-exome sequencing on normal mouse tissues for four weeks, and found
that Notch1 signaling activation played a key role in the multi-step
carcinogenesis of mouse thymic lymphoma, which laid the foundation for a
better understanding of the multi-step carcinogenesis mechanism of
hematologic malignancies after TBI(Lee et al., 2021). Irradiated mice
with different intensities of X-ray and analyzed the samples to study
the mechanism of radioactive leukemogenesis, revealing that abnormal
regulation of Sfpi1/PU.1 is an important step in the development of
induced AML(O'Brien et al., 2020). Multiple murine strains develop
leukemia on exposure to high and low-grade radiation, including the
C57BL, BALB/c and NFS mouse.

C57BL mouse has become widely used in the laboratory since 1921. In the
early years, C57BL mice were irradiated with different radiation doses,
and the optimal dose for inducing thymic lymphoma was determined(Kaplan,
1952), the incidence of leukemia/lymphoma was 15\% to 19\%(Lieberman \&
Kaplan, 1959). In recent years, radiation-induced C57/BL mouse models
have been used to study the mechanism of radiation
carcinogenesis(Takabatake et al., 2008) and the relationship between
changes in the thymic microenvironment and radiation-induced
leukemia/lymphoma development(Tsuji et al., 2013). Since 1932, BALB/c
mice have been widely used in animal experiments in immunology and
physiology(Potter, 1985), and have played a pivotal role in studying the
mechanism of radiation-induced tumors. In the radiation-induced BALB/c
mouse model, it was discovered that the tumor suppressor gene miR-21 was
involved in radiation-induced carcinogenesis(Liu et al., 2011). The
inbred NFS mouse is an inbred strain of the NIH Swiss mouse. The unique
advantage of the NFS mouse strain is that the genetic information of the
virus is not expressed under normal conditions and the expression of the
virus genes induced by radiation is easier to be detected. Similar to
the induction method of BALB/c and C57BL mice, NFS mice received 1.7Gy
irradiation 4 times a week to induce leukemia/lymphoma from 1 month-old.
Leukemia first appeared in NFS mice approximately 3 months after
irradiation, and most mice developed leukemia 4 to 6 months after
irradiation. The incidence of leukemia is 90\% in females and 89\% in
males. In addition, approximately 10\% of this strain develop
spontaneous thymic lymphoma(Ihle, 1978).

\textbf{4.3 Virus -Induced ALL Animal Models}

AKR mice are susceptible to leukemia and murine leukemia viruses(Mulv)
have been widely used to simulate human leukemia in susceptible mouse
strains(Rein, 2011). In the 1950s, Dr. Charlotte Friend injected the
MuLV supernatant from the spleen suspension of leukemia-affected AKR
mice into newborn mice to induce leukemia in adult Swiss mice or DBA/2
mice and cause serial transmission(Friend, 1957). Lymphoblastic leukemia
and lymphoma caused by retroviral insertion mutations can be used to
characterize new genes related to the occurrence of lymphoid leukemia by
describing the virus insertion sequence, and confirming misregulation of
several Notch signaling genes (Weiser et al., 2007).

Leukemia caused by C-type RNA tumor viruses or retroviruses is mostly
T-cell type. If the body's control system is out of control, this tumor
virus can turn hematopoietic cells into leukemic cells under the action
of reverse transcriptase, resulting in adult T-cell leukemia. Bovine
leukemia virus (BLV) and human T-cell leukemia virus type 1 (HTLV-1)
make up a unique retrovirus family. Both viruses cause
lymphoproliferative disease, with BLV affecting the B-cell lineage and
HTLV-1 affecting the T-cell lineage(Aida, Murakami, Takahashi \&
Takeshima, 2013). BLV can infect a variety of cell lines(Graves \&
Ferrer, 1976) and spread to rats(Altanerova, Portetelle, Kettmann \&
Altaner, 1989), pigs, goats and sheep(Mammerickx, Portetelle \& Burny,
1981)artificially. It is estimated that HTLV-1 has infected 5 to 10
million people worldwide and is a causative agent in adult T-cell
leukemia/lymphoma (ATLL), as well as other inflammatory diseases(Gallo,
Willems \& Hasegawa, 2016; Martin, Tagaya \& Gallo, 2018; Sodré Barmpas
et al., 2019). Researchers injected HTLV-1-infected cell lines into NOG
mice intraperitoneally, and other groups were given IR-treated HTLV-1
donor cells. Studies have found that the expression of Tax oncoproteins
was up-regulated, and its relationship with Extracellular Vesicles (EVs)
had a potential role in continuation of Tax-mediated pathogenesis, and
ultimately promoted the development of ALL(Pinto et al., 2019). Tax
oncoprotein enhanced uncontrolled replication of T cells and cellular
genes (such as IL-2/IL-2R), disrupted DNA repair mechanisms, causes
genetic instability, inhibits apoptosis of infected cells, and
interferes with cell cycle checkpoints(Ahmadi Ghezeldasht et al., 2013;
Currer et al., 2012). In addition, the levels of
CD4\textsuperscript{+}and CD8\textsuperscript{+} T cells in peripheral
blood were significantly increased, indicating that HTLV-I infection in
peripheral blood may cause the virus to invade CD4\textsuperscript{+}
and CD8\textsuperscript{+} T cell populations, as well as cells of the
monocyte/macrophage cell line(Anderson et al., 2018; Knight, Macatonia,
Cruickshank, Rudge \& Patterson, 1993). These models are helpful for the
identification and function of ALL-associated proto-oncogenes,
facilitating us to better understand the mechanisms of virus-induced
leukemia, helping to develop new strategies aimed at limiting virus
transmission, and playing a huge role in promoting the development of
virus-induced leukemia treatment strategies.

\textbf{5.}

\textbf{Xenotransplantation ALL Animal Models}

Since the culture system cannot replicate the complex interaction
between leukemia cells and the bone marrow microenvironment, it is very
difficult to culture and expand clinically aggressive patient-derived
leukemia cells \emph{in vitro} . The rate of cancer metastasis and cell
characteristics may change depending on the culture environment. To
overcome these limitations, researchers transplanted primary ALL cells
and cell lines into immunodeficient mice and developed mouse xenograft
models. The establishment of xenograft models is essential to study the
molecular mechanisms of human leukemia and to improve treatment options
by simulating human disease in animals for a more extensive evaluation
of human ALL.

\textbf{5.1 Experimental animal pretreatment}

Before ALL cell transplantation, the experimental animals should be
pretreated to produce bone marrow suppression and immunosuppression,
thereby reducing or eliminating the immune rejection reaction of immune
cells to human cell implantation and improving the success rate of
transplantation. The common pretreatment modalities nowadays mainly
include \selectlanguage{greek}γ-\selectlanguage{english}ray total body irradiation (TBI), injection of cytotoxic drugs
and administration of natural killer cell monoclonal antibodies to
experimental animals. TBI can significantly improve the success rate of
transplantation, the success rate of transplantation with TBI was
91.7\%, while without TBI it was only 15.4\%(Patel et al., 2014).
However, mice treated with high-dose TBI have high mortality, while
low-dose TBI resulted in low cell implantation rate. Therefore,
injection of cytotoxic drugs is more common. The study found that when
NSG mice were given a TBI dose of 2.4Gy, the survival rate at week 24
was only 33\%, while the survival rate of NSG mice that received a large
dose of busulfan was 100\% at week 24(Choi et al., 2011).Anti-CD122
antibody pretreatment is also commonly used, which can inhibit the
activity of natural killer(NK) cells and target NK cells and
macrophages, thereby exerting an immunosuppressive effect(Yuan, Dong,
Tsurushita, Tso \& Fu, 2018).

Transplantation donors generally choose immune-deficient mice aged 4-5
weeks and the main methods of transplantation are subcutaneous
injection, tail vein injection and intraperitoneal injection. The number
of cell inoculation is generally
10\textsuperscript{6}-10\textsuperscript{7} per mouse. Mice generally
show symptoms of slowness, paralysis, and curvature of the spine in
about three weeks, and leukemic cell infiltration can be detected in
peripheral blood, bone marrow, liver, spleen, lung and meninges.

\textbf{5.2} \textbf{Humanized Mouse Models}

\textbf{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).

\textbf{5.2.2 The} \textbf{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 \emph{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).

\textbf{5.2.3 The Non-obese Diabetic/Severe Combine Immunodeficient
(NOD/SCID) Mouse}

To overcome the problem of low transplant success rate in SCID mice,
researchers combined the SCID background mice with a non-obese diabetic
(NOD) strain to create a mice strain with more severe
immunodeficiency(Prochazka, Gaskins, Shultz \& Leiter, 1992) that
provided a supportive microenvironment for normal and malignant human
hematopoietic cells. NOD/SCID mice lack of functional T or B cells, and
the activities of NK cells and macrophages are reduced(Nagamoto et al.,
2015), a variety of tumor cells can be implanted, immune rejection and
graft-versus-host disease are less likely to occur. Therefore, NOD/SCID
mice have gradually become a useful tool for hematological experimental
research.

Researchers have made a breakthrough through the NOD/SCID ALL model and
found that a shorter ''time to leukemia (TTL)'', that is, the time from
transplantation to the appearance of leukemia is closely related to the
high risk of early relapse. The proliferation of neonatal ALL cells
transplanted into NOD/SCID mice has predictive value for patient
prognosis, thus determining an independent prognostic factor(Meyer et
al., 2011). TTL\textsuperscript{short} means TTL is less than 10 weeks,
and longer time periods are classified as TTL\textsuperscript{long}.
TTL\textsuperscript{short} identifies patients with early relapse, while
TTL\textsuperscript{long} relapse-free survival is as high as 100\%. The
NOD/SCID ALL model provides a powerful tool for identifying prognostic
factors in acute leukemia at the cellular and molecular levels, thus
providing a rational target for therapeutic strategies. The intact
apoptotic body function reflected by a positive Cytochrome c-related
activation of caspase-3 (CRAC positive) is closely associated with
long-term implantation of NOD/SCID (TTL\textsuperscript{Long}) in
primary leukemia cells and a good prognosis. The complete formation and
function of apoptotic bodies means that the time of NOD/SCID
implantation is prolonged, the treatment response is good, the prognosis
is good, and the patient survives without recurrence(Queudeville et al.,
2012). To determine disease prognostic factors, the NOD/SCID mouse model
has also played an important role in exploring novel drug targets. ATLL
is an aggressive disease that is highly resistant to chemotherapy. Due
to the high expression of KU70 in Jurkat cells, the researchers injected
Jurkat cells which knocked out of the KU70 gene into NOD/SCID mice,
discovered that KU70 may be a new target for ATLL treatment and help to
overcome chemo-resistance(Yu, Li, Wang, Zhang, Xu \& Liang, 2018).
Another xenotransplantation method is to extract hematopoietic
progenitor and stem cells (HP/HSCs) from patients or mice, transduce the
cells through reverse transcription or lentivirus, and then transplant
them into the recipient. Researchers transplanted
CD34\textsuperscript{+} hematopoietic progenitor cells and stem cells
(CD34\textsuperscript{+}HP/HSCs) from patients infected with HTLV-1 into
NOD/SCID mice, which specifically developed CD4\textsuperscript{+}T-cell
lymphomas similar to ATLL, and increased proliferation of virus-infected
human stem cells (CD34\textsuperscript{+}CD38\textsuperscript{-}) in
mouse bone marrow was observed. This model provides an important tool
for identifying the molecular mechanism of the occurrence and
development of leukemia/lymphoma, exploring potential therapeutic
targets for inhibiting tumor development and evaluating the role of
HTLV-1 helper genes in the pathogenesis of the virus(Banerjee et al.,
2010).

NOD/SCID mice are host that are more receptive to the proliferation of
human leukemia, however, the high transplantation rate of T-ALL cells
suggests that this model fails to identify risk groups, and the
researchers found that human-derived T-ALL cells appear to be more
readily transplanted in NOD/SCID mice, suggesting that this model may be
more useful than SCID mice in studying the biology and treatment of
T-ALL(Steele et al., 1997). NOD/SCID mice have lower immune function and
higher tumor formation rate. More importantly, this model retains the
morphological, phenotypic and genotypic characteristics of ALL
donors(Bonnet \& Dick, 1997). However, this mice strain will also have
``leakiness''. Due to the development of thymic lymphoma and the
recovery of NK cell activity, it cannot be implanted for a long time,
and usually the implantation time cannot exceed 8.5 months(Shultz et
al., 1995).

\selectlanguage{greek}\textbf{5.2.4 The NOD/LtSz-scid with
IL2γ\textsubscript{c}\textsuperscript{null} (NSG) Mouse}\selectlanguage{english}

NSG mouse strain is an immunodeficient mouse that knocks out the
interleukin 2 receptor gamma chain (IL2R\selectlanguage{greek}γ\selectlanguage{english}) gene on the basis of
NOD/SCID(Ito et al., 2002). This mice strain lacks mature T and B
lymphocytes and completely loses NK cell activity(Koller \& Smithies,
1989). Compared with NOD/SCID mice, the transplantation survival rate of
human cell and tissue in NSG mice is significantly improved, and at the
same time, a higher proportion of normal or cancerous human cells and
tissues can be implanted.

The NSG mouse xenograft model is considered the gold standard for
evaluating human hematologic malignancy grafts(Sontakke et al., 2016)
and is widely used to assess disease pathogenesis and explore potential
therapeutic strategies. Researchers have used the NSG mouse
xenotransplantation method to elucidate the leukemia-initiating cell
(LIC) biology of pre-B ALL in order to optimize the disease model.
Different \emph{in vivo} growth requirements were determined between
adult and child ALL subtypes, and the importance of age/leukemia subtype
specific research was discovered. This animal model improves our
understanding of the biology of ALL disease(Patel et al., 2014). In
addition, the NSG model is also used to evaluate the effect of cytokines
on leukemia. Studies have shown that IL-27 can promote the proliferation
and differentiation of CD34\textsuperscript{+} cells in non-leukemia
patients(Seita et al., 2008), suggests that the cytokine may have an
effect on normal hematopoietic stem cells. Based on this, researchers
injected pediatric leukemia cell samples intravenously into NSG mice
for\emph{in vivo} studies to evaluate the anti-tumor activity of human
IL-27. IL-27 reduces the angiogenesis potential of tumor cells,
regulates tumor spread-related genes, and exerts an anti-tumor
effect(Zorzoli et al., 2012). In recent years, cellular immunotherapy
has proven to be an effective treatment for B-cell malignant hematologic
diseases. T cells modified with CD19-specific chimeric antigen receptors
(CARs) have significant clinical advantages for the treatment of
leukemia. NSG mice model is also an excellent tool for evaluating the
superiority of CAR-T therapy, and it has been demonstrated that a
lentiviral vector targeting CD8 (CD8-LV) could generate CD19-CAR T cells
in NSG mice(Pfeiffer et al., 2018). Recently, researchers have made
further progress by using CD4-targeted lentiviral vector (CD4-LV) to
selectively produce CD19-CAR T cells in CD4\textsuperscript{+} cells
successfully. Transplanted Nalm-6 cells which encoded by
CD19\textsuperscript{+} luciferase into NSG mice and injected activated
PBMCs cells. According to the luciferase intensity measured by
the\emph{in vivo} imaging system (IVIS) to evaluate the growth, spread
and regression of leukemia in the body, it was found that the mice given
CD4-LV showed faster and better tumor cell killing ability, indicating
that CD4\textsuperscript{+}CAR-T cells have a stronger ability to
eliminate tumor cells(Agarwal, Hanauer, Frank, Riechert, Thalheimer \&
Buchholz, 2020).

Xenograft models provide powerful tools for studying normal and
malignant human hematopoietic systems. However, current models cannot
simulate the human bone marrow (BM) microenvironment, and many human
leukemia cells cannot be xenotransplanted. In order to overcome these
limitations, scientists have used new advances in the field of
bioengineering and synthetic material development to manufacture
biological inserts or scaffolds that support the growth and
differentiation of implanted cells effectively(Abarrategi, Mian,
Passaro, Rouault-Pierre, Grey \& Bonnet, 2018). Implanted ceramic
scaffolds containing mesenchymal stromal cells (MSCs) into NSG mice to
generate a human bone marrow (huBM-sc)-like niche and observed that AML
MLL-AF9\textsuperscript{+} and ALL BCR-ABL\textsuperscript{+} patient
cells were efficiently implanted, maintaining an immature primitive
cell-like phenotype in the huBM-sc ecotype compared to the murine bone
marrow (mBM) niche(Sontakke et al., 2016). Later, based on the discovery
that human bone marrow mesenchymal stromal cells (BM-MSC) transplanted
into heterotopic NSG mice can rebuild the functional hematopoietic
microenvironment(Reinisch et al., 2015), the researchers mixed human
bone marrow BM-MSC with extracellular matrix and transplanted
subcutaneously to form a humanized bone marrow microenvironment in the
ossicle after 8-10 weeks. The implantation level of normal human HSCs
and leukemia cells containing subcutaneous humanized ossicles model is
much higher than that of untreated mice, and direct intraosseous
transplantation accelerates cell implantation and leads to an increase
in the frequency of leukemia initiating cells(Reinisch et al., 2016).
The scaffold implantation approach can evaluate the multicellular
interactions between human MSCs and HSCs, and generate patient-specific
human microenvironment in mice, which can be used to unravel the human
tumor microenvironment, disease pathology and the role of drug
physiological response(Abarrategi, Mian, Passaro, Rouault-Pierre, Grey
\& Bonnet, 2018).

\textbf{6.} \textbf{Transgenic ALL Animal Models}

Traditional transgenic(Tg) animal model is to inject the DNA fragments
into the pronucleus of the fertilized egg directly, and then into the
pseudopregnant female mice(W\selectlanguage{ngerman}ürtele, Little \& Chartrand, 2003),or
injected DNA into embryonic stem (ES) cells through
electroporation(Thomas \& Capecchi, 1987). In order to more accurately
simulate the occurrence of leukemia, homologous recombination is used to
generate vectors targeting specific sites in the genome. These vectors
conditionally express genes in response to doxycycline (Tet ON/OFF
system) or Cre recombinase (using Lox/Cre system) to produce
tissue-specific expression of transgenes, and chromosomal translocations
can be produced in mice through Cre-loxP-mediated recombination(Drynan
et al., 2005; Forster et al., 2003), thereby mimicking the chromosomal
translocations that often lead to the formation of tumor-specific fusion
oncogenes in human malignancies(Corral et al., 1996). In addition to the
expression of oncogenes, oncogenic alleles can also be ''knocked in'' to
the corresponding normal loci, or ''knocked out'' of tumor suppressor
genes to establish transgenic animal models. In recent years, transgenic
animal models have played a huge role in the general study of ALL
subtypes, including B-ALL, T-ALL, and Burkitt's leukemia/lymphoblastic
lymphoma, facilitating the discovery of drug targets and improving the
treatment of leukemia, which will be described in detail in the
following.

\textbf{6.1 BCR-ABL}

\textbf{transgenic models}

The BCR-ABL fusion protein is the result of t(9;22)(q34;q11)
translocation, which is common in CML, but can also be found in B cell
ALL. There are several isoforms of this fusion protein, including the
P210 form and the P190 form, with the P120 form progressing to B and T
lymphoma or myeloid leukemia after a longer latency period and the P190
form progressing to B-ALL(Voncken, Kaartinen, Pattengale, Germeraad,
Groffen \& Heisterkamp, 1995).

Researchers injected patients' BM cells which transfected with MSCV
BCR-ABL1 lentivirus into C57BL/6 mice, and used this mouse model to
determine the important role of tumor suppressor \selectlanguage{greek}γ-\selectlanguage{english}catenin in the
initiation and maintenance of BCR-ABL1\textsuperscript{+}B-ALL,
determining the potential therapeutic target for the treatment of
BCR-ABL1\textsuperscript{+}B-ALL(Luong-Gardiol et al., 2019).
Cyclin-dependent kinase (CDK) is a promising drug target in cancer
treatment, the loss of CDK8 significantly prolonged disease latency and
inhibited disease progression(Menzl et al., 2019). Through the BCR-ABL
transgenic mouse model, researchers found that CDK8 played a key role in
B-ALL, and degradation of CDK8 might be a potential therapeutic strategy
for the treatment of ALL. InLong non-coding RNAs(lncRNA)-Iur knockout
transgenic mice, researchers explored the functional relevance between
aberrantly expressed lncRNAs and BCR-ABL-mediated leukemia(Wang et al.,
2019).

This model has explored the effect of obesity on the progression of ALL.
For the first time, it was found that obesity could accelerate the
development of ALL, in a controlled experiment between BCR/ABL
transgenic mice and high-fat diet AKR/J mice(Yun et al., 2010). In
addition, this model was also used to test the activity of tyrosine
kinase inhibitors. The 8093ALL cell line was established in the
background of P190 BCR-ABL transgenic mice and transplanted into
C57BL/6J mice. It was found that nilotinib was significantly more
effective than imatinib and was able to eliminate a significant number
of ALL cells \emph{in vivo} (Kaur et al., 2007). Later, researchers
induced BCR-ABL expression in mice by the Tet-OFF system, and treatment
with nilotinib reduced the number of leukemic cells and prolonged
survival in mice. This suggests that combined inhibition of BCL-2 and
BCL-ABL tyrosine kinases has the potential to significantly improve the
cure rate of CML, while tyrosine kinase inhibitors targeting BCL-2 and
BCL-ABL can overcome this limitation of disease relapse(Carter et al.,
2016). These findings are of great significance for adjusting clinical
treatment plans and improving patient prognosis.

\textbf{6.2 MLL-AF4 transgenic models}

The MLL-AF4 fusion protein is seen in patients with t(4;11) and it is
strongly associated with B-ALL. As early as 1996, J Corral et al. fused
the AF9 sequence into the mouse MLL gene, and used the method of
embryonic stem cell homologous recombination to create an MLL-AF9 gene
knock-in model, and the chimeric mice carrying the fusion gene produced
tumors(Corral et al., 1996). Based on the success of this model,
researchers established an MLL-AF4 ''knock-in'' transgenic model in
which the majority of Mll-AF4 mice developed B-cell lymphoma after a
long latency period(Chen, Li, Hudson, Kumar, Kirchhof \& Kersey, 2006).
In order to establish a mouse model more similar to human MLL-AF4, the
researchers microinjected MLL-AF4 MSCV into the pronuclei of eggs from
C57BL/6N Crj mice and established an MLL-AF4 transgenic mouse model by
high expression of the human MLL-AF4 fusion gene. This is the first
transgenic mouse to test the potential of human MLL-AF4 fusion protein
to induce B-cell lymphoma/leukemia(Tamai et al., 2011). The
above-mentioned MLL-AF4 Tg mouse models have also proved the
effectiveness and feasibility of gene therapy for
MLL-AF4\textsuperscript{+}ALL and the specific mechanism, gene therapy
is a promising strategy for the treatment of
MLL-AF4\textsuperscript{+}ALL(Tamai et al., 2012). Later, the
researchers evaluated the potential of the anti-allergic drug amlexanox
to improve the clinical efficacy of MLL-AF4\textsuperscript{+}ALL and
found that amlexanox reduced the resistance of
MLL-AF4\textsuperscript{+}ALL to TNF\selectlanguage{greek}α \selectlanguage{english}by down-regulating the expression
of S100A6(Tamai et al., 2017).

Another model was generated using an inverted AF4 allele targeted to an
intronin the MLL gene. An AF4 cDNA flanked with loxP sites inserted in
reverse orientation into the endogenous MLL locus,and
then,cell-specific Cre expression was used to generate Mll-AF4
expression. Regardless of whether the Cre gene is controlled by a B-cell
or T-cell promoter, mice develop B-cell lineage tumors only, but their
phenotype is more mature than that normally observed in childhood
leukemia(Metzler et al., 2006).

\selectlanguage{greek}\textbf{6.3 Eμ-Myc transgenic models}\selectlanguage{english}

Burkitt lymphoma/leukemia is a subtype of ALL, which is characterized by
chromosomal translocation leading to Myc gene expression under the
control of immunoglobulin heavy chain or light chain promoters. Myc
oncogenes are usually highly expressed in human T-ALL(Erikson et al.,
1986). Under the control of the IgG heavy chain promoter, the mouse Myc
gene produces transgenic mice that mimic the clinically seen
t(8;14),most of the mice suffer from B-cell lymphoma/leukemia(Harris,
Pinkert, Crawford, Langdon, Brinster \& Adams, 1988).

Researchers established three Myc transgenic mouse models. According to
the level of Myc, the tumor phenotypes of Myc mice are different, with
high expression leading to rapid-onset T-cell lymphoma, low expression
leading to late-onset myeloid tumors, and moderate expression levels
producing both tumor types(Campbell, Vandenberg, Anstee, Hurlin \& Cory,
2017). Later, analyzed the gene expression and function of senescent and
non-senescent B-cell lymphomas in E\selectlanguage{greek}μ-\selectlanguage{english}Myc transgenic mice, researchers
found that previously senescent cells \emph{in vivo} presented a higher
tumor initiation potential. It is worth noting that in p53-regulated ALL
and AML models, temporary strengthening of senescence can reprogram
non-stem bulk leukemia cells into self-renewing, leukemia-initiated stem
cells. These findings have far-reaching implications for cancer
treatment(Milanovic et al., 2018). Recently, in order to analyze the
important role of the microenvironment in regulating human AML
population dynamics, researchers investigated the effects of oncogene
(c-Myc) and exposure to cytokines such as IL3, GM-CSF and SCF on human
AML cells in immunodeficient mice. This finding emphasized the key role
these cytokines play in activating normally differentiated human
hematopoietic cells(Bulaeva et al., 2020). The leukemia induced by these
methods have rapid and powerful reproducibility, which provides a useful
and powerful platform for testing and evaluating new treatment
medication in human acute leukemia.

\textbf{6.4 NOTCH1 transgenic models}

NOTCH1 was first identified in the human T cell ALL-bearing
translocation, t(7;9)(q34;q34.3). Activation of the NOTCH1 signaling
pathway is the most important tumorigenic event in the pathogenesis of
T-ALL(Weng et al., 2004), and this gene is related to the pathogenesis
of most T-cell ALL types.

Researchers established a mouse bone marrow transplant (BMT) model in
which Cre recombinase induces HSCs Notch activation, thereby inducing
T-ALL in mice. The activation of Notch in HSCs leads to the expansion of
hematopoietic progenitor cells and T cell precursor cells, and then the
production of HSCs and T cells is gradually lost. The over-activated
Notch signal in HSCs promoted the leukemia stem cell (LSC) activity of T
cell precursor cells and inhibited the self-renewal of HSCs. This
conditional transgenic model provides further evidence for T-ALL
targeting, and also emphasizes the necessity of strictly regulate Notch
signaling to expand the normal HSC population for clinical
applications(Chiang, Shestova, Xu, Aster \& Pear, 2013). Later, the CD4
promoter was used to express NOTCH1 mutants in Tg mice, including
Notch1\textsuperscript{IC} and Notch1\textsuperscript{EC} produced by
type I mutations, and Notch1\selectlanguage{greek}\textsuperscript{ΔCT}\selectlanguage{english} produced by type II
mutations, double (Notch1\textsuperscript{IC}\selectlanguage{ngerman}× myc) or
(Notch1\selectlanguage{greek}\textsuperscript{ΔCT}\selectlanguage{english}\selectlanguage{ngerman}×myc) Tg mice developed thymoma with a much
shorter latency than single Tg mice, providing genetic evidence of a
collaboration betweenthese two oncogenes. These Notch1 mutations are
very similar to some forms of human T-cell leukemia, and these Tg mice
may represent relevant models of these human leukemias(Priceputu et al.,
2006). The NOTCH Tg model also plays an important role in the evaluation
of drug efficacy. Researchers investigated the drug sensitivity of T-ALL
cells in Notch1-induced CD8\textsuperscript{+}CD4\textsuperscript{+} and
CD8\textsuperscript{+}CD4\textsuperscript{-} cell subsets in T-ALL mice
and examined the sensitivity of
CD8\textsuperscript{+}CD4\textsuperscript{+} and
CD8\textsuperscript{+}CD4\textsuperscript{-} to cyclophosphamide and the
mTORC1 inhibitor rapamycin. They found that the combined use of
cyclophosphamide and rapamycin reduced the number of leukemia cells and
prolonged the lifespan of T-ALL mice compared with the use of drugs
alone. This indicates that the combination of cyclophosphamide and
rapamycin is expected to improve the clinical treatment of NOTCH-induced
T-ALL(Zhang et al., 2013).

\textbf{7.} \textbf{Non-mouse Models}

Insights into the pathophysiology of leukemia have been obtained in
non-mouse models. These different animal models help us to understand
the underlying mechanisms of leukemia treatment resistance and disease
relapse, and are expected to improve treatment strategies.

Zebrafish's conservative hematopoietic system and unique experimental
advantages, combined with the development of transgenic, genome editing
and xenotransplantation technologies, reveal the details of
leukemogenesis, progression and regression(Harrison, Laroche, Gutierrez
\& Feng, 2016). Zebrafish has become an attractive model for research on
drug screening for hematological malignancies(Idilli, Precazzini, Mione
\& Anelli, 2017). The first zebrafish T-ALL model was created in 2003 by
fusing the mouse c-Myc gene with the Enhanced Green Fluorescence Protein
(EGFP) gene, and the lymphocyte-specific promoter rag2 drove the
expression of the EGFP-mMyc fusion gene, resulting in T-ALL in
zebrafish(Langenau et al., 2003). Later, the researchers modified the
model and induced it with 4-hydroxy tamoxifen, and the Myc gene was
activated, causing T-ALL in zebrafish(Gutierrez et al., 2011; Langenau,
Feng, Berghmans, Kanki, Kutok \& Look, 2005). In addition to the T-ALL
model induced by Myc gene, researchers also successfully established a
zebrafish T-ALL model by overexpressing the human NOTCH1 gene under the
rag2 promoter(Sabaawy, Azuma, Embree, Tsai, Starost \& Hickstein, 2006).
Zebrafish are rapidly expanding our understanding of disease mechanisms
and helping to develop treatment strategies to improve the prognosis of
patients with leukemia. Based on the progress of zebrafish in
high-throughput drug screening, it is expected to accelerate the
development of novel leukemia therapeutic medications.

Rats are sometimes used when establishing carcinogens and radiation
induced leukemia models(Huggins, Grand \& Ueda, 1982; Svejda, Kossey,
Hlavayova \& Svec, 1958). It is reported that repeated injection of DMBA
into Wistar rats, which induced 10\% of rat leukemia in 5-9
months(Huggins \& Sugiyama, 1966). A subline of inbred Sprague-Dawley
rats has a high incidence of T cell malignancies and has been used for
preclinical evaluation of treatment(Bua et al., 2018; Otová, Sladká,
Panczak \& Marinov, 1997). Drosophila has a strong hematopoietic
capacity, and its genetic simplicity and ease of manipulation make it an
attractive model for studying leukemia caused by complex chromosomal
translocations. In order to study the detailed molecular mechanism of
leukemia caused by the AML1-ETO chimeric protein, two AML1-ETO
drosophila models were established using genetic engineering
technology(Lebestky, Chang, Hartenstein \& Banerjee, 2000). Later,
researchers found in Notch-induced drosophila tumor models that Notch
signaling and PI3K-AKT pathway have a synergistic effect in
tumorigenesis. The transcriptional control of PTEN and the regulation of
the PI3K-AKT pathway are key elements of the leukemia progress activated
by NOTCH1. These findings provide the basis for the design of new T-ALL
treatment strategies(Palomero et al., 2007).

\textbf{8. Summary and Prospect}

It is undeniable that animal models have played a huge role in revealing
the mechanism of tumorigenesis and evaluating new drugs. It not only
avoids the huge risks that may be caused by human trials, but also
provides a safe and reliable method for leukemia research. More
importantly, animal models provide an experimental platform for testing
the efficacy of novel therapeutic compounds on human ALL and for
studying drug resistance mechanisms. To sum~up, these models provide a
basis for drug development, screening and testing. And ultimately, they
provide a basis for individualized treatment.

The advantage of the spontaneous model is that the clinical symptoms are
more similar to those of human tumors, and the conditions for tumor
occurrence are more natural. However, the etiology of the spontaneous
model is different from that of humans, and is mainly caused by genetic
factors. Moreover, this type of model is easily affected by
environmental factors, may cause disease complications, and has poor
stability. In the past, chemistry, irradiation and viral models have
played a significant role in ALL research and have been used to discover
and evaluate ALL drugs. The tumorigenesis mechanisms of the induced
animal model are clear, and the tumorigenesis rate is relatively high.
However, this type of model is unstable and has a high fatality rate.
Due to species differences, the pharmacodynamic results of these animal
models are not conducive to derivation of human medications. In order to
better simulate human diseases, researchers implanted humanized tumor
cells into immunodeficient mice and established xenograft models, which
have now become the main tool for studying ALL, providing us with the
opportunity to observe the entire process of the development and
regression of lymphocytic leukemia and may play a crucial role in
clinical. The advantages of xenotransplantation are that the model is
easy to establish, the speed of tumor formation is fast, and the
clinical manifestations are similar to those of human leukemias,
especially in terms of histopathology, immunohistochemical phenotype and
karyotype. The transgenic model has obvious practicality in preclinical
drug efficacy testing and exploring the interaction of matrix-immune
cells. The advantages of transgenic models are that, these models
overcome the problem that xenograft models cannot better simulate the
microenvironment of tumor cell growth, and can accurately simulate human
leukemia. These have made transgenic models have been successfully used
to screen for and test novel targets and inhibitors. The major
disadvantage is that there is a certain difference in interstitial
components between mice and humans. In addition, transgenic animals are
expensive, and the tumor formation process is complicated. We list the
advantages and limitations of the various animal models in Table 1.

Evaluating therapeutic targets in transgenic and xenograft models is
expected to enter clinical trials to improve the lives of leukemia
patients. In future, advances in genome editing technology and
cooperation in multidisciplinary fields will promote the production of
more humanized mouse strains, which will help researchers to simulate
the complex biology of ALL in mice more accurately. Ultimately, the use
of many bioengineering models and continuous efforts to improve their
effectiveness and physiological relevance will push preclinical research
into a new era of targeted treatment development.

\textbf{Acknowledgments}

This research was supported by the National Natural Nature Science
Foundation of China (No. 81973332), the Research Fund of Anhui Institute
of translational Medicine (No. 2021zhxyB01), the Key Projects of Natural
Science Research of Anhui Colleges and Universities (No. KJ2020A0158)
and Improvement Program of Scientific Research Basement Construction
(No. 2021xkjT043).

\textbf{Competing interests}

The authors declare that they have no competing interests.

\textbf{Author contribution}

Qianling Xin wrote the manuscript and created the figures, all authors
developed the outline, discussed, edited, and approved the manuscript.

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an official journal of the American Association for Cancer Research
18\textbf{:} 1630-1640.

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