LEUKAEMOGENESIS — VIRAL AND CYTOLOGICAL ASPECTS 75 



leukaemia (CML) revealing the "Philadelphia" chromosome (Ph^), a minute 

 autosome (probably No. 21) with a terminal deletion of the long arm. It is 

 also noteworthy that individuals with Down's syndrome, in whom the 

 incidence of acute leukaemia is many times higher than normal (Carter et al., 

 1956; Krivit and Good, 1956; Stewart, 1961), are trisomic for the same 

 autosome. These facts have prompted the speculation that chromosome-21 is 

 important in the regulation of haemopoiesis in man (Tough et al., 1961), 

 although no specific and consistent abnormalities of this chromosome have 

 been noted in leukaemias other than CML or in Down's syndrome. 



Exciting as these observations may be, and however strongly they may 

 suggest a chromosomal basis for the pathogenesis of certain types of leukae- 

 mia, it must be cautioned that such an interpretation remains conjectural. It 

 is important, for example, to determine the frequency of abnormalities of 

 chromosome-21 in other diseases and in normal individuals and to learn 

 whether Ph^ may be detected in advance of the onset of CML. As yet, no 

 abnormalities of chromosome-21 have been reported in normal individuals, 

 although the number of the latter examined is still relatively small. It may 

 also be inquired why trisomy for chromosome-21 in mongolism should 

 predispose to leukaemias mainly of the acute type, whereas a terminal 

 delection of the same chromosome should be associated with only CML in the 

 absence of mongolism. Possibly the difference may be related to the dosage of 

 the unbalanced chromosome (monosomy versus trisomy) or to the disparity 

 in age and tissue distribution (post-zygotic and confined to blood cells versus 

 pre-zygotic and present in all cells of the body). These and other questions 

 must be answered before the cytogenetic aspects of leukaemia can be fully 

 evaluated. The occurrence of erythrocyte mosaicism in leukaemic individuals 

 (Tovey, 1960; Salmon et al., 1960) may be another indication of genetic 

 instability of haemopoietic cells associated with leukaemia, as may differences 

 in the antigenic specificity of leukaemia cells (Gorer and Amos, 1956). 



Another question raised by these cytogenetic findings is the possible 

 aetiologic influence of chromosomal aberrations in radiation leukaemogenesis. 

 For example, can the induction of CML in irradiated human beings be 

 attributed to radiation-induced breakage of chromosome-21 and formation 

 of a Ph^ through a terminal deletion? From the frequency of spontaneous and 

 radiation-induced deletions in human blood cells (Table V), the incidence of 

 natural and radiogenic leukaemia seems too low to be accounted for by such 

 a one-hit mechanism alone, as argued previously (Brues, 1958, 1959). 

 Alternatively, one might attribute leukaemogenic changes to more complex 

 chromosomal aberrations or to multiple point mutations in the genome of the 

 myeloblast. The latter possibilities are being examined by Burch (1962, 

 personal communication), who argues that many tumours, including 

 leukaemias, develop in adult humans from a generating cell with four mutant 



