Leukaemia in the CNS niche regulates PI3K/Akt signalling via upregulation of miR-93 in MLL-AF4+ infant leukaemia

Abstract

One of the unique clinical features of infant leukaemia is a high rate of central nervous system (CNS) disease, typically a leukaemic infiltrate of the meninges. Using a fully murine MLL-AF4+ infant leukaemia model (Malouf et al. Blood 2021), which develops this characteristic leukaemic infiltrate of the meninges, we performed RNA sequencing to identify niche-specific drivers of CNS leukaemia. Differential gene expression analysis of BM and CNS-derived leukaemia identified genes involved in PI3K/Akt signalling pathway specifically Pten and Cdkn1a. We confirmed these findings on a protein level and showed CNS-derived leukaemia cells have increased activation of this pathway. In silico mRNA-miRNA analysis identified the miR-17-92 family as potential regulators of this interaction. We profiled the miR-106b-25 cluster within this family and found upregulation of miR-93 in CNS-derived leukaemia cells. Subsequent analysis of MLL-AF4+ infant leukaemia patient-derived xenografts have mirrored the miR-93 expression pattern found in our model. Further work is underway to understand the niche-specific functional importance of miR-93 and its potential as a biomarker for CNS leukaemia.