Title

Disrupted niche function for normal hematopoiesis in AML is restorable with IL-1R antagonist therapy

Abstract

The acute myeloid leukemia (AML) ecosystem comprises leukemia cells, normal hematopoietic stem and progenitor cells (HSPCs), and niche cells that together shape disease progression and therapeutic responses. The cellular interactions between the leukemia-permissive niche and the HSPC population are not yet well understood. Here, we leveraged in-depth, single-cell RNA sequencing and spatial transcriptomics to map hematopoietic disruptions under leukemia stress. In AML, bone marrow (BM) HSPCs displayed restricted erythroid and megakaryocytic differentiation and instead a bias toward myeloid lineages. We also identified a novel LSKlow (Lin-Sca1+cKitlow) cell population in AML with multi-lineage reconstitution potential. Cell-cell interaction analysis revealed weakened stem cell factor (SCF)-KIT signaling between niche cells and HSPCs, which likely reduces hematopoietic support in AML. Conditional Scf knockout in BM stromal cells shortened survival in AML mice, whereas intra-BM injection of SCF (via adeno-associated virus) prolonged survival. Further analysis revealed downregulation of hematopoietic-supportive factors and upregulation of pro-inflammatory factors in BM stromal cells. Elevated inflammatory signal IL-1 likely mediated the transcriptional regulation of SCF in AML, as administering an IL-1 receptor antagonist (Anakinra) restored Scf expression and functions in stromal cells and improved normal hematopoiesis, thus extending the survival of AML mice. Our single-cell atlas of the AML ecosystem provides a resource for future analyses to explore therapeutic targets, including the SCF-KIT and IL-1 axis, aimed at restoring the supportive functions of the hematopoietic niche in AML.