LEUKAEMOGENESIS — VIRAL AND CYTOLOGICAL ASPECTS 77 



incidence at Hiroshima of leukaemia in adults — two specific chromosome 

 breaks followed by a translocation and deletion could be genetically 

 equivalent to three "point" mutations. Most of the Hiroshima victims, 

 except for those in the highest age range, were, he suggests, carriers of an 

 inherited mutation predisposing to a particular malignancy or group of 

 malignancies, including leukaemia. Childhood and adolescent malignancies 

 are said to arise from a cell with three mutant control genes, one of which 

 is normally inherited, together with a condition of "stress ". The latter 

 condition may be either a stimulated proliferation of generating cells or an 

 infective oncogenic virus. In all aetiologies, Burch suggests that hormonal 

 agents or an immune reaction complete the transformation from the carci- 

 nogenic to the malignant cell. According to his theory, two loci on each of the 

 homologous chromosomes of pair 21 must be affected concurrently to cause 

 leukaemia. With such a premise as a working hypothesis, a variety of radia- 

 tion dose-leukaemia incidence curves may be calculated, depending on the 

 number of somatic mutations pre-existing in myeloblasts at the time of 

 irradiation (which is presumably age-dependent) and on the conditions of 

 exposure. 



On the other hand, the indirect induction of lymphomas in non-irradiated 

 mouse thymus cells obviously cannot be attributed to any type of radiation- 

 induced cytogenetic changes since the cells are not themselves irradiated. The 

 two situations, therefore, imply either different mechanisms of leukaemia 

 development or common intermediate aetiologic pathways yet to be defined. 



Cell turnover rates 



The availability of isotopic tracers, especially ^H-thymidine, has facilitated 

 determination of the rate of growth of leukaemia cells. Studies of leukopoiesis 

 to date fail to support the theory that the leukaemia cell divides more rapidly 

 than its normal haemopoietic counterpart (see Cronkite et at., 1960; Gafosto 

 et al., 1960). On the contrary, the data are consistent with a normal or even 

 prolonged germination time of leukaemia cells. Hence, it may be inferred 

 that leukaemic growth involves arrested maturation and unstable, quasi- 

 exponential reproduction of non-differentiating stem-cells rather than a 

 simple acceleration of cell division. As yet, however, precise quantitative data 

 are too scanty to allow a precise mathematical formulation of neoplastic 

 proliferation. 



One of the most timely studies, therefore, is to characterize the kinetics of 

 blood cell formation, survival, and elimination in leukaemias of various types 

 and to contrast these characteristics with the normal state. It is conceivable 

 that the elimination of leucocytes, as well as their maturation, is impaired in 

 leukaemia, although early suggestions to this effect have not been substan- 

 tiated (see Hauschka and Furth, 1959). 



