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Leukaemia cell intrinsic and extrinsic factors cooperate to facilitate the survival and proliferation of KMT2A-rearranged B-ALL in the CNS niche.

ABSTRACT: Infant B-cell acute lymphoblastic leukaemia (B-ALL) is a rare, aggressive entity characterised by KMT2A-rearrangements and poor outcomes. One of the unique features of KMT2A-rearranged infant ALL contributes to these poor outcomes is a particularly high rate of central nervous system (CNS) involvement. In this study we used an immune competent KMT2A-AFF1+ infant B-ALL murine model (https://doi.org/10.1182/blood.2020006610) to explore the cell-intrinsic and cell-extrinsic mechanisms that underpin this clinically significant complication. We show novel functional impacts on leukaemia propagating cells (LPCs) following exposure to the CNS niche which results in unique leukaemia repopulation dynamics. Transcriptomic and immune cell profiling comparisons by niche showed differences in the immune microenvironment between the CNS and bone marrow (BM) niches. We observe the CNS niche demonstrates supressed T cell and macrophage activity which may be part of a wider CNS niche-specific immune escape mechanism. Our transcriptomic comparisons by niche also led us to explore the role of PI3K pathway activation in the propagation of leukaemia cells within the CNS niche. We identify miR-93 as a possible master regulator of this process. The importance of miR-93 is emphasised as it is shown to be upregulated in CNS leukaemia cells across multiple murine KMT2A-AFF1 B-ALL model systems and in primary KMT2A-AFF1 B-ALL patient samples. We conclude by showing impaired CNS engraftment of leukaemia cells upon miR-93 knockdown, cementing its importance in CNS leukaemia biology.

ORGANISM(S): Mus musculus

PROVIDER: GSE280505 | GEO | 2026/04/12

REPOSITORIES: GEO

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