SeminarAetiology of acute leukaemia
Section snippets
Biological diversity and aetiology
Acute leukaemia, like other cancers, is a progressive clonal disorder driven by mutations. An extraordinary diversity of chromosomal and molecular changes occurs in leukaemic cells, and the restriction of most to the leukaemic clone itself suggests that these are acquired, not inherited. However, a small but significant proportion (up to 5%) of acute leukaemias (both myeloid and lymphocytic) are associated with inherited, predisposing genetic syndromes, often involving genes encoding functions
Established causal factors
Although the cause of most acute leukaemias is not known, certain major factors have been implicated in some cases.
Ionising radiation, certain types of chemicals, especially organic solvents (benzene),3 and at least one virus (HTLV-I) can contribute to leukaemogenesis as agents or major risk factors. Long-standing observations in experimental animals and cells in vitro have shown an association between leukaemogenesis and damage to DNA and/or cellular transformation by these same agents.
Risk from ionising radiation
The best substantiated causal mechanism for acute leukaemia is via ionising radiation. Much of the current understanding and risk estimates are based upon the Life Span Study, which documented the incidence of acute leukaemia (and chronic myeloid leukaemia [CML]) following the atomic bombing of Nagasaki and Hiroshima in 1945.4 Leukaemia has also been associated with occupational exposures to ionising radiation of the early radiologists and radiation scientists,5 including Marie Curie and her
Therapy-induced or “secondary” leukaemias
Radiotherapy and many agents used in chemotherapy for malignant and non-malignant disease are genotoxic and induce DNA strand breaks. Iatrogenic leukaemogenesis is thus, to recall a phrase from the Gulf War, like being hit by friendly fire. Nevertheless, the potential benefits from genotoxic therapy considerably outweigh the risks.
Secondary malignancies attributable to genotoxic therapy are predominantly acute myeloid leukaemias.16 At increased risk of AML are children treated for ALL or
Topoisomerase II function, DNA breaks, and leukaemia
The type I and type II topoisomerase (topo I, II) enzymes catalyse breakage and resealing of DNA, a function that prevents tangling of helical, duplexed DNA strands during replication.20 The anthracyclines and epipodophyllotoxins exert their cytotoxic effect by stabilising the reaction intermediate produced during the breakage of double-stranded DNA by topo II. This intermediate, the cleavable complex, consists of drug plus topo II protomer bound to the broken 5′ ends of DNA strands. At high
De-novo acute leukaemias with 11q23/MLL gene rearrangements
11q23/MLL gene rearrangements with one of more than 30 potential chromosomal partners21 are observed in de
novo ALL, AML, and mixed-lineage (lympho-myeloid) acute leukaemias, and they generate novel hybrid genes. Deletions or duplications within the MLL gene may also occur. Karyotypic analysis has suggested that 11q23 abnormalities occur in about 5% of childhood and adult de-novo acute leukaemias, but more recent techniques, molecular analysis (using FISH, RT-PCR, and Southern blot) reveal a
Infection and childhood acute leukaemia
The concern that childhhood and other leukaemias might be caused by some form of infection is almost as old as the clinical recognition of disease but lost appeal when it was appreciated that leukaemia was not contagious. More recently, the idea has been resurrected, partly because of the realisation that most spontaneous leukaemias in domesticated animals (chickens, cats, and cattle) are viral in origin, and partly because of the role of Epstein-Barr virus in Burkitt's lymphoma and HTLV-1 in
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