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Acute myeloid leukemia (AML) encompasses a highly heterogeneous group of clonal disorders arising in hematopoietic progenitors that are characterized by a block in differentiation and outgrowth of myeloid blasts giving rise to bone marrow failure. Although AML is not particularly common, affecting approximately 3 individuals per 100 000 population per year in Western countries (i.e. ~2000 new cases per year in the UK), it is challenging and expensive to treat, representing a significant burden on healthcare systems. Given that AML is predominantly a disease of the elderly, with markedly higher incidence in individuals over 60 years of age, this disease is set to become an increasing problem as the population ages.
Molecular basis of AML
The last three decades have witnessed major advances in deciphering the cytogenetic and molecular lesions underlying the pathogenesis of AML. These have not only afforded significant insights into disease biology, but also proved helpful in providing prognostic information and underpinned the development of molecularly targeted and risk-stratified treatment approaches. A further benefit of improved understanding of the molecular basis of AML coupled with the development of sensitive quantitative polymerase chain techniques has been the possibility to assess treatment response at the submicroscopic level (i.e. detection of minimal residual disease, MRD), thereby affording the opportunity to tailor therapy more precisely to the needs of the individual patient.
In 1977 we (L. M. A. and R. C. A.) submitted our first research proposal to the National Institutes of Health. The most speculative part was to use in situ hybridisation techniques to determine the distribution of individual mRNAs in sea urchin embryos. We suggested that information on spatial distribution would be useful in approaching three questions. First, we were puzzled that molecular assays of gene expression in whole embryos had led to the generalisation that most mRNAs are found throughout development (reviewed by Davidson, 1976, 1986) and that a relatively small percentage show large changes in abundance on a per embryo basis. The missing information required to interpret these observations was the extent to which genes are spatially regulated in different tissues or lineages. Second, we hoped to identify sets of mRNAs whose expression is co-ordinated in time and space, so that the mechanism of that co-ordination could be investigated. Third, we suggested that individual spatially restricted mRNAs could serve as molecular markers to construct a fate map of the embryo, to determine when cells commit to specific patterns of gene expression, and possibly to identify maternal RNAs localised in the egg. We proposed a longterm commitment to ‘localise the time and site of synthesis of individual mRNA species in developing embryos’. A dozen years seems an appropriately long time, and we take this opportunity to review the contribution of information gained from in situ hybridisation studies to the questions we initially anticipated, as well as to some we did not.
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