There are three current hypotheses concerning infectious mechanisms in the aetiology of childhood leukaemia: exposure in utero or around the time of birth, delayed exposure beyond the first year of life to common infections and unusual
population mixing. Till now, no specific virus has been definitively linked with childhood leukaemia and there is no evidence to date of viral genomic inclusions within leukaemic cells. Nevertheless, case–control and cohort studies have revealed equivocal results. Maternal infection during pregnancy has been linked with increased risk whilst protective roles were determined to be breast feeding and day care attendance in the first year of life.
There is debate from studies on early childhood infectious exposures, vaccination and social mixing. Some supportive evidence for an infectious aetiology is provided by the findings of space-time clustering and seasonal variation of acute leukemia new cases presentations..
Spatial clustering suggests that higher incidence is associated with specific areas with increased levels of population mixing, particularly in previously isolated populations. Ecological studies have also shown excess incidence with higher population mixing.
The marked childhood peak in resource-rich countries and an increased incidence of the childhood peak in acute lymphoblastic leukaemia (ALL) (occurring at ages 2–6 years predominantly with precursor B-cell ALL) is supportive of the concept that reduced exposure to early infection may play a role.
In addition, genetically determined individual response to infectious agents may be critical in the proliferation of preleukaemic clones as evidenced by the human leucocyte antigen class II polymorphic variant association with precursor B-cell and T-cell ALL (McNally1and Eden ,2004).
Previous data led by Greaves (1999) has demonstrated that for certain types of acute leukemia as infant ALL with MLL rearrangements, mostly in the precursor B-cell ALL (certainlyTEL-AML1 and hyperdiploid ALL) and childhood AML with t(8;21) translocations, the first genetic event in childhood leukaemia involves production of a preleukaemic clone in utero. Greaves (1999) hypothesized that whatever the cause of the gene rearrangements in utero, postnatal events including infection are almost certainly required to promote the development of clinical leukaemia.
These data has clearly defined the need for at least two and possibly multiple postnatal events. Therefore, when considering aetiology the initiating events occurring most frequently in utero and subsequent events occurring postnatally are important. Whether infection plays a part at either or both time-points is unclear.
It is claimed that the first ‘genetic’ event might well be initiated by infection. However, all the studies to date have shown no evidence of viral genomic inclusion in leukaemic cells. Thus, the suggestion that maternal infection during pregnancy may be associated with an increased risk of childhood leukaemia would be supportive of such a relationship (Smith et al., 1997).
The hypothesis includes the possibility that infection might occur in utero or near to birth. The space time clustering data based on time and place of birth would clearly be consistent with events in utero (Kinlen’s et a. 1988 and 1995).
The findings from space-time clustering studies from the UK and Sweden (Gustafsson & Carstensen, 2000, McNally et al, 2002) support the in utero exposure, clearly in the most recent time period.
Obviously there is quite a lot of supportive data to suggest that the later postnatal events are indeed related to infections and/or the body’s response to them. Evidence from the geographical incidence and temporal increases in the incidence of childhood leukemia is consistent with lack of immune stimulation during the first few years of life, particularly in more affluent communities and societies.
The limited and protective effect of breast feeding and more significantly, the apparent benefit of increased social contact because of nursery attendance in the first year of life would again be supportive of the concept that leukemia is more likely if there is an absence of infectious exposure early in life and that leukemia results from some form of delayed and possibly abnormal response to infection at a later age.
The host factor represented by HLA class II allele linkage to precursor B-cell ALL is further corroborative evidence. Space-time clustering studies centered on time and place of diagnosis are also consistent with the delayed infection hypotheses, as are those based on time of diagnosis and place of birth and also Kinlen’s studies on unusual population mixing.
It is very important to realize that the population mixing hypotheses are not mutually exclusive. Elements of both may be involved in individual cases. Infection may initiate a preleukemic clone but that may not lead to overt leukemia in the absence of delayed later infection and/or abnormal response to such infection. Controversely to benefits of population mixing this may increase the chance of infectious exposure in susceptible people at any stage.
At the present time, in the absence of definitive evidence regarding either specific single or multiple infectious culpable agents at either time-point, it is beneficial to continue to investigate events and exposures around the two time-points and the molecular events that result from such exposures.
Greater clarification as to likely etiological agents may emerge. For
example, in infant leukemia, where very characteristic rearrangement of the MNLL gene occurs, there has been both epidemiological and molecular evidence to suggest that exposure to naturally occurring topoisomerase II inhibitors and the inability by the mother and fetus to metabolize them rapidly significantly increases the risk of developing leukaemia.
Topoisomerase II reduces DNA damage that is inappropriately repaired. A combination of exposure, DNA damage and inappropriate repair plus failure to metabolize the inhibitors all contributes to the initiation of a rare leukemia.
So we can say that there may be a multiple pathways involved in the development of any childhood leukemia that will always involve initial breakage and inaccurate repair of DNA in response to infection, chemicals, low level irradiation or other, as yet unknown, environmental exposures. Then one or more subsequent events convert a preleukaemic clone into an overt malignant population. Two genetic events and possibly also proliferative stimuli and/or suppression of bone marrow are all required to produce an overt leukaemia.
Another important issue is the genetic susceptibility. It looks likely in terms of not only the response to infection, but also the recognition and repair of DNA.
The study of the molecular events associated with leukemia transformation may help us to better understand the changes.
However, at present we are still some time away from measures that would enable us to subtly target therapy or indeed apply preventative measures based on a clear understanding of causation, including immune modulation of response to infection.
One of the implicated virus in development of acute leukemia is PB19. It is suggested that the interaction between PB19 and host immune response has a role. Acute parvovirus infection is associated with a significant cytokine cascade, which is associated with a degree of disturbed haematopoiesis and/or suppression of normal marrow function, which may allow ‘release’ of low level malignant clones or indeed, induce acute leukemia. Serum concentrations of TNFα and IFNγ are typical of symptomatic acute B19 infection.8 Greatly raised serum concentrations of IL-6 and GM-CSF have previously been documented at the onset of acute leukaemia.9,10 The chemokine MCP-1 is released by leukaemic cells; it is chemotactic for monocytes and induces the tumoricidal activity of monocytes, and is thus a possible host defence against neoplasia.16 B19 virus infection is associated with the suppression of erythroid elements in the bone marrow, along with immune cell proliferation and upregulation of key mediators, such as GM-CSF. Such mechanisms may play an important role in the conversion of preleukaemic clones to an overt leukaemia.
Parvovirus and hematological disorders in children
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