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 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.
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).