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).