# Integrative spatial multi-omics reveal niche-specific inflammatory signaling and differentiation hierarchies in AML

## TL;DR

This study uses spatial multi-omics to map how AML cells are organized in bone marrow and extramedullary sites, revealing how inflammation and signaling influence their location and behavior.

## Contribution

A novel workflow for Visium-based spatial transcriptomics in AML, revealing spatial organization and inflammatory signaling in distinct niches.

## Key findings

- Primitive-like AML cells localize near bone, while committed-like cells reside in inflamed regions.
- CXCL12-CXCR4 signaling links AML cells to inflammatory niches and activates PI3K/AKT/mTOR pathways.
- Inflammation drives niche remodeling and T cell dysfunction in AML microenvironments.

## Abstract

Acute myeloid leukemia (AML) is a clonal disorder characterized by immature blasts and arrested differentiation that primarily affects the bone marrow (BM) and occasionally presents as extramedullary (EM) disease. EM manifestations highlight AML’s adaptability to distinct microenvironments, which we examined using spatial analyses of medullary and EM tissues. We describe a workflow for Visium-based spatial transcriptomics in medullary and EM AML, revealing insights into cell-cell communication and the spatial organization of AML hierarchies. In BM, monocytes and granulocyte-monocyte progenitors colocalized with leukemic populations, sharing molecular signatures with those in EM sample. CXCL12-CXCR4-mediated communication correlated with PI3K/AKT/mTOR signaling in inflammatory niches. Trans-differentiation signals concentrated in AML-infiltrated regions; committed-like AML cells resided in inflammatory niches distant from trabeculae, while primitive-like cells localized near the endosteal niche. GeoMX digital spatial profiling and Opal multiplex fluorescent immunohistochemistry provided orthogonal validation. Overall, our study offers a valuable multimodal resource for exploring AML spatial biology with potential applications in other BM malignancies.

•Spatial multi-omics maps AML states in bone marrow and extramedullary sites•Primitive AML cells localize near bone; committed-like cells in inflamed regions•Inflammation drives AML niche remodeling and T cell dysfunction•CXCL12-CXCR4 signaling axis links AML cells with their microenvironment

Spatial multi-omics maps AML states in bone marrow and extramedullary sites

Primitive AML cells localize near bone; committed-like cells in inflamed regions

Inflammation drives AML niche remodeling and T cell dysfunction

CXCL12-CXCR4 signaling axis links AML cells with their microenvironment

Components of the immune system; Proteomics; Transcriptomics