LEUKAEMOGENESIS: QUANTITATA^E ASPECTS AND CO-FACTORS 5 



Thus the cells of developed leiilvaemia have a genetic character different 

 from the normal and the unsolved question is how this difference is acquired. 

 The cause of a genetic change is not necessarily primarily genetic. 



It is as well to note that the evidence suggests that leukaemic cells of 

 chronic leukaemias divide more slowly (not faster) than the corresponding 

 normal cells, and that the accumulation of abnormal cells in these varieties 

 of leukaemia is due to their abnormally long survival time. As is true of all 

 forms of neoplasia, the body's control of the rate of cell division of leukaemic 

 cells is an imperfect control. It is a false definition of cancer to say that it is 

 uncontrolled growth. 



LEUKAEMIA AS A RARE EVENT 



Leukaemogenesis, like carcinogenesis, must be a rare event in cellular 

 terms. If leukaemia originates in one cell — and, since a developed leukaemia 

 can sometimes be transmitted by grafting a single ceU, this hypothesis cannot 

 be dismissed out of hand — then only one cell in the 1-5 kg of active bone- 

 marrow in a human adult need be changed in order that myeloid leukaemia 

 should develop. If all 10^^ myeloid cells capable of proliferation are susceptible 

 of leukaemia induction then the probability of action of an inducing agent 

 causing a 100% incidence of leukaemia is 10~^^ per cell (Brues, 1959). If only 

 one in 10,000 of these cells is susceptible of a leukaemic change, the probability 

 would be 10"'^: how far back one goes in a cell lineage before finding "suscept- 

 ible" cells is quantitatively very important. If leukaemia is thought to 

 originate not in a single cell but in a field of cells, the required probability for 

 a whole field of 1 mm^ would stiU be about 10~^. 



There is also an element of rareness about the kind of leukaemogenic (or 

 carcinogenic) events which follow irradiation. Single doses of 5 to 50 r may 

 produce gross degrees of physiological damage (Table I) but doses of several 

 hundred to several thousand r or more are needed to produce large (--^50%) 

 incidences of leukaemia or cancer. Radiation must be much more efficient in 

 killing cells or in interfering with their ability to multiply (their so-called 

 reproductive integrity) than m causing malignant transformation of individual 

 cells or of small foci of cells. 



This observational fact should make one very cautious about applying 

 to leukaemogenesis and carcinogenesis the results and ideas derived from the 

 radiobiological experiments on cell populations. In ceU-survival experiments 

 information on the effect of dose-rate and LET and oxygen tension is derived 

 from the whole population of cells which retain the ability to divide. On the 

 other hand, if irradiation of cells can induce leukaemic (or cancerous) changes 

 directly, what is relevant to leukaemogenesis (or carcinogenesis) is the infor- 

 mation cormng from the small fraction of the whole surviving popidation in 



