REFORMAS QUE CONSOLIDAN EL NEOLIBERALISMO AVANZADO

The term ‘blast’ refers to the morphology of a subpopulation of progenitors that are the earliest, most immature cells committed to the myeloid or lymphoid lineages, before the appearance of the definitive characteristics of the cell (Encylopedia, 2016). Morphologically, blasts usually form around 5% of cells in a normal healthy bone marrow. When blasts represent more than 20% of the cells of a specific lineage, it is considered to be a pathological status known as leukaemia (Harris et al., 1999). Leukaemia is further divided into subgroups. The first division separates acute and chronic forms of leukaemia followed by a subdivision based on the type of blood progenitor cells affected. This results in either lymphoblastic or myeloid leukaemia (Harris et al., 1999).

Acute lymphoblastic leukaemia (ALL) is the most commonly occurring paediatric cancer and accounts for 80% of all childhood leukaemia. ALL is a

heterogeneous disorder affecting both adults and children, with a peak prevalence in children of between the ages of 2 and 5 years (Pui et al., 2008). It is characterised by the malignant proliferation and clonal expansion of lymphoid progenitor cells arrested at an immature stage of differentiation in the T and B cell lineages. Although remarkable progress has been made in the treatment of ALL, with 5-year event free survival rate exceeding 90%, it still remains one of the main causes of cancer deaths in children (Pui et al., 2011). Furthermore, in developed countries the incidence of ALL has increased consistently by 1% a year over the past two decades (Linabery and Ross, 2008). The genetic events underlying the induction of ALL include aberrant expression of proto-oncogenes, chromosomal translocations and hyperdiploidy and hypodiploidy (Chen et al., 2010). These genetic alterations in blood progenitor cells committed to T or B cell differentiation promote leukaemic transformation by altering crucial cellular functions. For example, they maintain or enhance unlimited self-renewal capacity of these committed progenitors, subvert their normal proliferation controls, block differentiation at specific stages and promote resistance to apoptosis (Pui et al., 2004). A few cases (<5%) of ALL are associated with inherited, predisposing genetic syndromes, such as Down’s syndrome, Bloom’s syndrome and ataxia-telangiectasia. The majority of ALLs are represented by a pre-B cell phenotype, displaying cell surface marker expression associated with normal pre-B cells. The leukaemic cells are blocked at this particular stage of the differentiation process and accumulate in the body (Inaba et al., 2013).

Chromosomal translocations affecting specific genes are a defining characteristic of acute lymphoblastic leukaemia, in particular. These translocations sometimes result in the erroneous joining of two chromosome breaks, generating a fusion gene whose function is dissimilar to its wild type counterpart. ALL associated

fusion genes mainly encode active kinases or altered transcription factors (Pui et al., 2008). Many of these altered transcription factors control cell differentiation and frequently encode proteins at the apex of crucial transcriptional pathways. These oncogenic transcription factors are expressed aberrantly in leukaemic cells and can exist as one gene product or as a fusion protein combining two different transcription factors that play critical roles in normal haematopoiesis. Studies that examined gene- expression patterns in different leukaemias demonstrate that specific chromosomal translocations define unique disease subtypes (Fig. 4) (Pui et al., 2008).

1.6 ‘Delayed infection’ hypothesis

One model to explain the induction of frank leukaemia in ALL suggests that an abnormal immune response to common pathogens can result in malignant transformation. Based on this idea, two different possible hypotheses were suggested (Greaves, 2006b). One mechanism, the Kinlen ‘population mixing’ hypothesis, was generated when in the early 1980s clusters of childhood leukaemia were observed in specific areas of England and Scotland (Kinlen, 1988). The ‘population mixing’ hypothesis stated that increased incidence of childhood leukaemia might have infectious origins due to unusual population mixing that occurred when isolated communities in Seascale and Thurso accommodated a sudden influx of migrant professional workers. People in isolated places may escape exposure to common infections in the usual age groups, and therefore are relatively ‘non-immune’ to these infections. Therefore, it was suggested that some childhood leukaemia clusters were an unusual outcome of common infections in these non-immune individuals, following contact or ‘population mixing’ with newcomers who are carriers of infections (Greaves, 2006b; Kinlen, 1988). Kinlen made a parallel comparison

between the communities of Seascale and Thurso to a ‘rural’ new town of Glenrothes with no migrant influx, to note a threefold transient increase in the incidence rate of childhood leukaemia, as measured by mortality statistics (Kinlen, 1988). Although in Kinlen’s studies most patients had ALL, the data supporting this hypothesis could be interpreted to show that all childhood and infant leukaemia could share a common aetiology.

The second hypothesis was proposed in 1988 and is known as the ‘delayed infection’ hypothesis (Greaves, 1988). This model sought to explain the peak age prevalence of leukaemia between 2 and 5 years and at the time suggested a ‘two-hit’ model, which has now gathered substantial evidence. The ‘two-hit’ model proposed that the chromosomal translocation (first hit) was insufficient to induce overt leukaemia but rather acts as an initiating event resulting in pre-leukaemic cells that persist for years before onset of leukaemia, resulting from further acquisition of secondary genetic mutations (second hit). The ‘delayed infection’ hypothesis proposed that in affluent societies, many children have reduced exposure to common infectious agents during infancy. This predisposes the immune systems of such children to aberrant or atypical immune responses following ‘delayed’ infectious exposure to these common infections. These aberrant immune responses can provide a microenvironment that promotes secondary mutations, which then act as a trigger for progression of pre-leukaemic clones into overt leukaemia. Although there is substantial epidemiological evidence supporting this hypothesis, there is limited experimental data to support the reasons behind higher ALL incidence upon infection in young children (Greaves, 2006b).