Leukaemia and the CNS Niche: Insights on Bidirectional Communication from a Model of Infant Leukaemia

Infant leukaemia, an acute leukaemia within the first year of life, is a rare, aggressive entity with a poor response to intensive therapy. MLL-AF4+ infant leukaemia, the most common genetic subtype, has been shown to have: an in-utero origin, a lack of co-driver mutations, and lineage plasticity. Central nervous system (CNS) disease, typically a leukaemic infiltrate of the leptomeninges, is particularly common in these patients compared with non-infant paediatric ALL, and presents a serious clinical problem. With increasing understanding of the diverse immune cell landscape in the meninges, we sought to use our recently developed fully murine infant leukaemia model to explore the interactions between leukaemia and this microenvironment.

We previously identified two microRNAs (miR128a and miR130b) that are upregulated in MLL-AF4+ infant and paediatric leukaemia patient samples. Overexpression of these microRNAs individually in mouse foetal liver (FL) Lin-Sca1+cKit+ (LSK) cells resulted in microRNA-dependent lineage-specific acute leukaemias in the context of Mll-AF4 with prominent CNS infiltration (Malouf et al. Blood 2021).

To identify potential niche-specific leukaemia-propagating cells in our Mll-AF4+ mir128a+ infant proB-ALL model, we performed serial transplants using sorted leukaemia progenitor populations (LSK IL7R+ and Lin-Sca1-cKit+ (LK/CLP)) from mice that had previously succumbed to leukaemia. We observed that these leukaemia progenitors were functionally identical with indistinguishable output. This suggests the leukaemia-initiating cells in this model can emerge from different cell populations, consistent with our current understanding of ALL-initiating cells in human disease. CNS leukaemia developed in these mice with features that also mirror human disease: an immunophenotypically polyclonal infiltrate of the leptomeninges, sparing the brain parenchyma.

To complement the functional data, we transcriptionally validated the infant proB-ALL model for two key features: foetal cell-of-origin and infant-specific expression signatures. Published RNA sequencing of murine FL and adult bone marrow (BM) lymphoid-primed multipotent progenitors (LMPP) - a putative cell of origin for infant leukaemia - were reanalysed (Symeonidou et al. Cell Reports 2021 data set). BM-derived leukaemia cells from our model are more similar to FL than adult BM LMPPs. Using a published MLL-AF4+ patient leukaemia data set we showed that cells from our model are also transcriptionally closer to infant than non-infant paediatric MLL-AF4+ ALL patient samples (Figure 1)(Andersson et al. Nature Genetics 2015 data set).

Transcriptomic differences were identified by RNA sequencing of leukaemia progenitors from the BM and CNS niche. Statistically significant Gene Ontology terms of particular interest based on these differences are summarised in Figure 2. Genes upregulated in CNS-derived cells included cell adhesion molecules, immune modulators and cell growth factor receptors. These suggest a CNS-specific adaptive response to the microenvironment in a bidirectional manner. These novel observations may represent infant leukaemia-specific adaptations or more generic CNS leukaemia interactions uncovered through the use of an immunocompetent fully murine disease model. In either scenario, the implications of bidirectional communication between leukaemia and the CNS niche are significant for the development of much-needed novel biomarkers and therapies.

No relevant conflicts of interest to declare.