miR-93-mediated PTEN suppression and CNS-specific T cell exhaustion shape the leukemia niche in infant KMT2A::AFF1+ B-ALL.

Infant B cell acute lymphoblastic leukemia (B-ALL) with KMT2A rearrangements is an aggressive disease with poor outcomes, partly due to a high rate of central nervous system (CNS) involvement. Limited understanding of the CNS niche's molecular and immune characteristics hinders the development of effective therapies, especially as current immunotherapies have reduced efficacy in this environment. Using an immune-competent KMT2A::AFF1+ infant B-ALL murine model, we identify unique functional and transcriptomic adaptations of leukemia within the CNS niche. We describe suppressed T cell and macrophage activity in the CNS, suggesting niche-specific immune escape mechanisms. Additionally, we demonstrate PI3K pathway activation as a key driver of CNS leukemia propagation through direct measurement of increased AKT phosphorylation and reduced PTEN expression, with microRNA (miR)-93 emerging as a regulator. We confirm miR-93 upregulation in patient samples, suggesting its suitability as a biomarker for CNS involvement. Critically, miR-93 knockdown impairs CNS leukemia engraftment, highlighting its niche-specific role.