CHROMOSOMES IN MURINE PRE-LEUKAEMIA 89 



if gene mutation is taken as the ultimate in carcinogenesis it is readily 

 appreciated why cells from all lymphomatous mice do not necessarily show- 

 gross structural mutation changes. It is also conceivable that structural 

 changes not capable of observation in this system, i.e. cryptostructural, are 

 present. Perhaps also we have been imfortunate not to observe small clones 

 of abnormal cells. 



The observation of twelve out of nineteen pre-leukaemic thymuses 

 containing one or other of the chromosomal structural anomalies with or 

 without an increase in the diploid set of chromosomes approximates our 

 experience of about 70% leukaemia-induction following irradiation. It has 

 been estimated on microscopic evidence alone that by 50 days after irradia- 

 tion virtually all thymic tumours are already apparent (Nagareda and Kaplan, 

 1958) although deaths due to dissemination did not begin until 120 days (110 

 days in our series). Combining these two sets of data one can imagine that 

 leukaemia in situ or pre-leukaemia is present relatively early after irradiation 

 but as shown by selection of cases with no macroscopic evidence of leukaemia 

 (under 70 mg thymic weight), established leukaemia capable of transplanta- 

 tion occurs much later. But chromosome changes are already apparent. 

 Importance must be attached to the observation of cells with deviations from 

 the rigid diploid set for we have seen departure from normal chromosome 

 complements excessively rarely (perhaps only once in a thousand cells or less) 

 except in malignant tissues. It is implied that there must also be a departure 

 from the normal amount of DNA. However, the significance of structural 

 changes alone as related to the induction of leukaemia is difficult to assess for 

 the same appearance has been seen often unassociated with neoplasia, e.g. in 

 haemopoietic tissue in radiation chimaerism where reversion has occurred 

 (Ford et at., 1957). But all the evidence suggests that these balanced 

 rearrangements involving neither loss nor gain of genetic material. A 

 priori it is the unbalanced changes (in which there is an alteration in the 

 amount of chromosome material through duplication or deficiency of whole 

 chromosomes) that are the more likely to be implicated in leukaemogenesis. 



In 3 of the 19 pre-leukaemic mice, clones of identical cells were dissemin- 

 ated throughout the tissues examined cytogenetically, i.e. thymus, spleen, and 

 bone-marrow and yet none of these separate organs on transplantation pro- 

 duced leukaemia. There are a number of instances of abnormal clones also 

 seen in haemopoietic tissue but not in thymus (Table I). Failure of the 

 homeostatic mechanisms (Furth and Yokoro, 1960) following the heavy 

 irradiation schedule may well allow the appearance of otherwise forbidden 

 clones. 



The majority of lymphocytic leukaemias with macroscopic involvement 

 "take". Despite efforts to make receptive hosts by the use of immature 

 recipients, thymectomized recipients and radiation chimaeras, pre-leukaemias, 



