Biological models for leukaemia and lymphoma

Blood-cell cancers (leukaemias, lymphomas and myeloma) are a very diverse group of neoplasms derived from a variety of stem cells at different hierarchical levels of haemopoietic and lymphoid cell development. This biological heterogeneity is likely to be associated with a variety of different etiological mechanisms. Correspondingly, a large number of inherited normal allelic variations might be expected to contribute to risk. Leukaemias alone have more than 200 different acquired (non-constitutive) molecular abnormalities but some are much more prevalent than others and are associated with biological subtypes with distinctive clinical or prognostic features. Balanced chromosome translocations are very common, together with simple gains or losses of chromosomes. Gene deletions and mutations are also relatively common, especially in more advanced disease. In several types of leukaemia and lymphoma, a transition from benign to malignant status can be tracked together with concurrent accrual of additional molecular abnormalities (e.g. chronic myeloid leukaemia evolving into blast crisis and follicular lymphoma becoming diffuse). The covert preclinical natural history of paediatric leukaemia has been revealed by 'back-tracking' using chromosomal translocation-gene-rated fusion gene sequences as clone-specific stable, specific and sensitive markers. Studies in identical twins, in archived neonatal blood spots of patients and in normal newborn cord bloods all support the contention that chromosomal translocations often initiate leukaemia in utero. Twin concordance rates (and animal modelling) suggest that further secondary genetic changes and exposures postnatally are, however, critical and this is endorsed by the finding that leukaemic fusion genes are present in normal newborn infants at a rate that far exceeds the cumulative risk of leukaemia. The natural history of leukaemic subtypes provides a useful framework for molecular epidemiological studies and significant advances have been made in this respect with infant and childhood acute lymphoblastic leukaemia.