Characterising the leukaemic microenvironment in a mouse model of infant AML with prenatal KMT2A-MLLT3 expression
Abstract
Infant acute myeloid leukaemia (AML) is an aggressive form of paediatric leukaemia diagnosed in children under two years of age. Infants with AML display distinctive clinical features, such as extramedullary infiltration, and experience high rates of relapse. Over 50% of infant AML cases are associated with rearrangements affecting the KMT2A (lysine methyltransferase 2A) gene, with the gene coding for the MLLT3super elongation complex subunit the most frequent fusion partner.
Bone marrow (BM) is a highly complex tissue containing many stromal and endothelial cell types which tightly regulate normal haematopoiesis, through secretion of soluble factors and cytokines to and from haematopoietic cells, as well as via direct cell-cell contact. It is becoming increasingly well recognised that these bidirectional cellular communication pathways are subverted in adult AML to support leukemic survival at the dispense of normal haematopoiesis. Given the prenatal origins of infant AML, it has been difficult to investigate these microenvironmental interactions due to the lack of faithful in vivo models which can recapitulate its prenatal origins.
We employed the previously described doxycycline-inducible KMT2A-MLLT3mouse model (Stavropolou et al., 2016) and induced KMT2A-MLLT3expression from embryonic day (E)12.5 onwards. KMT2A-MLLT3-expressing progeny succumbed to a lethal myelo-monocytic AML with leptomeningeal infiltration – a clinical feature enriched in the infant AML patient cohort…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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