72 ARTHUR C. UPTON 



extractable from the tissues of such mice at all ages (see Gross, 1961). If this 

 explanation is correct, the basis for the relatively long induction period of 

 spontaneous and radiogenic leukaemia remains enigmatic. 



That radiation may exert effects on host suscejDtibility other than of a 

 purely "virus-activating" nature is indicated by the enhanced sensitivity of 

 irradiated adult mice to the oncogenic effects of injected virus preparations 

 (Graffi and Krischke, 1956; Upton, 1959; Furth, personal communication). 

 This is also implied by the anti-leukaemogenic action of post-irradiation 

 marrow transplantation, which is effective even when carried out after the 

 last of four successive weekly whole-body radiation exposures (Kaplan et al., 

 1953). The mechanism by which marrow shielding or marrow infusion inhibits 

 leukaemogenesis remains to be established, but several investigators (Kaplan, 

 1961; Axelrad and Van der Gaag, 1962) have suggested that the effect is 

 mediated through enhanced regeneration of the irradiated thymus. According 

 to this hypothesis, radiation-induced depopulation of haemopoietic tissues 

 contributes toward the development of leukaemia by causing a protracted 

 hyperplasia of undifferentiated thymic stem-cells, which are postulated to be 

 preferentially susceptible to the oncogenic effects of leukaemia virus. How 

 intact marrow assists thymic regeneration is not yet clear, although there is 

 some evidence that marrow-derived stem-cells can repopulate the thymus 

 (see Popp, 1962). Whether the counteracting effects of urethane (Berenblum 

 et aL, 1961) operate through interference with thymus ceU maturation remains 

 to be explored, as does the jDossible role of immunogenetic mechanisms in the 

 anti-leukaemogenic action of intact marrow. 



These observations raise puzzling questions concerning the roles of radia- 

 tion, viruses, and host factors in leukaemogenesis. Although the available 

 information is stiU scanty, we can make tentative generalizations. 



1. Leukaemias of a wide variety of haematologic types can be induced in 

 fowl, mice, and rats by viruses (see Gross, 1961). 



2. Some radiation-induced lymphomas (Gross, 1958, 1959; Liebermann and 

 Kaplan, 1959) and myeloid leukaemias (Upton, 1960; Parsons et al, 1962) of 

 mice yield filterable leukaemogenic agents. 



3. Induction of leukaemias by irradiation is inhibited by the presence of 

 only a few non-irradiated heamopoietic cells (see Upton et al., 1960) and in 

 some instances the induction has been shown to occur entirely through 

 indirect mechanisms (Kaplan, 1959). 



4. Induction of leukaemias is also promoted in some instances by adminis- 

 tration of oestrogens (see Kaplan et al., 1954), urethane (Berenblum and 

 Trainin, 1960), or turpentine (Upton, 1959) after irradiation. 



5. Susceptibility to leukaemia induction varies markedly with age at time 

 of irradiation (Kaplan, 1948; Upton et al., 1960) and strain (see Upton and 

 Furth, 1957; Upton et al, 1958). 



