The viral etiology of the avian leukosis complex was established in 1908 by the work of Ellerman and Bang (1). However, it was not until over 40 years later that a similar relationship of viruses to certain of the murine leukemias was demonstrated.

Cross Leukemia Virus

In 1951 Gross (2) showed that acellular filtrates of the hematopoietic organs of AK mice, which had developed leukemia spontaneously, would induce the disease in mice inoculated shortly after birth.

One of the "fundamental features" of these studies was the use of mice less than 16 hours old as test animals. The results obtained with older mice were erratic, the incidence of leukemia low, and the latent periods greatly extended.

Under similar experimental conditions Gross (S) and Stewart (4, 5) later showed that the leukemic tissue filtrates would also produce tumors of the parotid gland and subcutaneous fibromyxosarcomas. Filtrates prepared from any one of these neoplasms reproduced all three tumor types upon reinoculation into susceptible hosts.

In 1957 Gross (6) reported the development of a highly active "Passage A strain" of leukemia virus. Originally derived from spontaneous AK leukemia, the agent was passed serially in newborn C3H mice. This passage material produced tumors in a greater percentage of inoculated mice in a shorter period than the original strain of the virus. Of particular interest is the additional finding by Gross (7) that the "Passage A" virus produced leukemia but not parotid-gland tumors in suckling and young adult C3H mice.

The recovery and cell-free passage of an X-ray activated leukemia agent in Bittner C3H mice has also been described by Gross (8-10). The relationship of the "Passage X" virus to the "Passage A" agent remains to be determined.

Physical data on the Gross virus indicate that it is inactivated at 65° to 68° C. and that it remains stable at -70° C. as well as under the conditions of lyophilization. A particle size of 50 to 70 vein, determined by sedimentation and electron microscope observations, has been reported by Gross (11). Dmochowski and Grey (12-14) and Bernhard and Gross (15) described the presence of particles in the virus-induced leukemic tissues and in extracts of these tissues. Although these particles varied in size and structure, the predominant elements, according to Bernhard et al., were of Type A ("doughnut"-shaped particles) with a diameter of 75 imi.

Immunological studies (10) with "Passage A" and "Passage X" leukemia filtrates have established that these materials elicit a neutralizing antibody response in a heterologous (rabbits host system. The presence of hemagglutinins in heat-inactivated "Passage A" leukemic tissue filtrates has also been described (16). The mouse erythrocyte agglutinin could be separated from the active principle of the filtrates by centrifuga-tion, which left open to question the direct relationship of the agglutinin to the tumor virus.

The histologic characteristics of the viral-induced leukemia were similar to those of spontaneous lymphocytic leukemia and to those of the lymphoid neoplasms induced by total-body X irradiation. McEndy et al. (17), Furth (18), and Law (19) have demonstrated that removal of the thymus gland decreases the incidence of spontaneous leukemia in normally high leukemic strains of mice. Kaplan (20) showed that thymectomy had an inhibitory effect on the incidence of radiation-induced lymphomas in C57BL mice. In addition, Gross (21) reported that thymectomy either prior to or after inoculation of "Passage A" leukemic filtrates inhibited the viral induction of lymphocytic leukemia in C3H mice.

Schwartz Leukemia Viruses

In 1957 Schoolman, Spurrier, Schwartz, and Szanto (22) described the recovery of a lymphoid leukemia-inducing agent from the brain tissue of a leukemic Swiss mouse. The virus produces generalized lymphocytic leukemia in their substrain of adult Swiss mice. Regardless of the route of inoculation, intraperitoneal or subcutaneous, the latent period was 1 to 3 weeks after virus inoculation.

Of particular interest is the observation that the virus could be recovered not from the lymphoid tumor but from the brain tissue of the infected mice. This fact and the unusually short latent period of the agent distinguish this virus in the mouse leukemia field. The agent is inactivated by heat (30 min. at 56° C.) and by formalin.

The gross pathologic findings, which differed from those of the AKR leukemia, were significant splenomegaly and hepatomegaly and frequent thymus enlargement; however, peripheral lymph-node involvement was slight. The outstanding observation was a massive involvement of the mesentery, which often extended to the urogenital organs.

A more recent report by Schwartz et al. (23) described the recovery of a similar leukemia-inducing agent from the brain of a C3HeB mouse with a spontaneous lymphoblastic leukemia. This agent has the same characteristics with regard to thermolability and filterability as those described for the Swiss mouse agent. The C3H agent is effective in adult mice of various C3H sublines and produces leukemia at a high incidence. The latent period is relatively short, usually not exceeding 46 days for the most resistant animals.