Understanding the role of ontogeny for the development of infant MLL-AF9 leukaemia

Abstract

Infant leukaemia (0-1 years) remains a challenge in the clinic and is likely a reflection of a still developing understanding of its origins. Specific to infants with acute leukaemia is an in utero origin and a disproportionally high incidence of MLL gene fusions [1]. These fusions are highly efficient transformation agents in foetal blood cells as additional mutational incidence is very low and increases with patient age [2, 3]. Interestingly, the MLL-AF9 fusion generates acute myeloid leukaemia (AML), acute megakaryocytic leukaemia (AMKL) and B-cell acute lymphoblastic leukaemia (B-ALL) in infants, despite causing only AML in adults [1]. Altogether, these data suggest that there are foetal contexts that provide a permissive platform for transformation and that afford MLL-AF9 increased lineage potential. It has been unclear where, when and what cell types can support infant leukaemia, which has impeded proper disease modelling. Previous work from the lab on MLL-AF4+ infant ALL uncovered a window of opportunity for leukaemogenesis between E12.5-E14.5 in the murine foetal liver (FL), revealing that FL HSPCs appear to have a particular sensitivity to MLL fusions within a restricted window of development [4]. Using a doxycycline-inducible mouse model of human MLL-AF9 expression (iMLL-AF9), which allowed us to express the fusion at any stage in vivo at physiological levels, I explored the replicability of this window of opportunity in infant AML [5]. Doxycycline (dox) induction from E12.5 resulted in mice developing AML with a median latency of 16 days that is of comparable age to human infants. This is, to my knowledge, the first model that initiates in utero and culminates in overt disease with a faithful latency for MLL leukaemia in mice. Furthermore, this latency is considerably shorter than that found in adult mice (118 days) and shows that this model is capturing an increased efficiency that MLL fusions have when arising in utero. In utero pre-leukaemia was characterised by a myeloid differentiation block that was effected at the level of GMP. Interestingly, birth triggered myeloid cell expansion and suggests that leukaemic progression is closely tied to mechanisms of HSPC development.