Abstract
ABSTRACTFor patients and their families, the diagnosis of infant leukaemia is devastating. This disease has not seen the improvements in outcomes experienced with other paediatric leukaemias and it is becoming ever more apparent that infant leukaemia is a distinct biological entity. Insights into some of the distinguishing features of infant leukaemia, such as a single mutation – the MLL-gene rearrangement, the biology of disease aggressiveness and lineage plasticity, and the high incidence of central nervous system involvement, are likely to be gained from understanding the interactions between leukaemic cells and their environment or niche. The origins of infant leukaemia lie in the embryonic haematopoietic system, which is characterised by shifting locations and dynamic changes in the microenvironment. Understanding this foetal or embryonic context is integral to understanding infant leukaemia development. Owing to its rarity and prenatal origins, developing accurate modelling systems for further investigation of infant leukaemia is essential. In this Review, we discuss how available in vitro, ex vivo and in vivo infant leukaemia models contribute to our current understanding of the leukaemia niche in embryonic development, established disease and specialised non-haematopoietic niches. The mechanistic insights provided by accurate models will help identify viable novel therapeutic options.
Highlights
Leukaemias are the most common type of childhood cancers; the opposite is true in children under the age of 1 year, where leukaemia is a relatively uncommon malignancy (Alfaar et al, 2017)
Our findings suggest that, during this stage of development, the foetal liver niche contributes to the initiation of MLL-AF4 infant leukaemia, a concept that will be discussed in more detail later in this Review
The evaluation of in vitro and in vivo models of infant and paediatric leukaemia, in which the haematopoietic niche has been a focus of analysis, proves that niche-dependent factors have significant impact on leukaemia initiation and lineage determination
Summary
Leukaemias are the most common type of childhood cancers; the opposite is true in children under the age of 1 year (infants), where leukaemia is a relatively uncommon malignancy (Alfaar et al, 2017). Evidence of definitive haematopoiesis has been found during the ‘second wave’ of blood production starting at E8.5, originating in the yolk sac and mainly being composed of erythro-myeloid progenitor cells (Frame et al, 2013) It is, only during the ‘third wave’ beginning at E10.5, that the first fully functional haematopoietic stem cells (HSCs) are formed. Sugiyama et al have highlighted the role of delta like noncanonical Notch ligand-positive (Dlk1+) hepatoblasts in supporting the proliferation of HSCs and the formation of erythroblastic islands necessary for the production of red blood cells within the foetal liver Their results demonstrated that Map2k4-deficient mice, which lack hepatoblasts, show reduced HSC proliferation. Foetal liver Colonisation of foetal liver by HSCs, followed by HSC expansion and differentiation, and establishment of the haematopoietic tree
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