FGF18 mediates fibroblast-leukemia cross talk to promote acute myeloid leukemia progression.

abstractNonhematopoietic stromal cells are essential regulators of hematopoiesis; however, their contribution to leukemogenesis and immune dysfunction remains poorly defined. In this study, we identified fibroblast-derived fibroblast growth factor 18 (FGF18) as a novel stromal cytokine that reprograms leukemia-immune interactions. Single-cell RNA sequencing of the bone marrow niche in acute myeloid leukemia (AML) revealed the upregulation of Fgf18 in stromal fibroblasts. Administration of recombinant FGF18 accelerated AML progression, whereas fibroblast-specific Fgf18 depletion markedly delayed disease development and improved the survival of mice. We performed a pooled CRISPR-Cas9 screen in AML cells and identified FGF receptor 3 (FGFR3) signaling as a critical mediator of leukemic fitness in the FGF18-rich microenvironment. Genetic loss of Fgfr3 in AML cells recapitulated the effects of FGF18 deficiency and limited leukemic expansion in vivo. Mechanistically, FGF18 binds to its receptor, FGFR3, on AML cells, activating the protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) (AKT-mTOR) signaling pathway and inducing interleukin-6 (IL-6) production. IL-6 acts autocrinely to reinforce leukemic signaling and paracrinely to activate fibroblast JAK-STAT3 signaling, thereby amplifying stromal fibroblast FGF18 expression and forming a feed-forward loop that suppresses CD8+ T-cell effector function and weakens antileukemic immunity. Clinically, elevated FGF18 expression correlates with poor prognosis in patients with AML. To therapeutically target this malignant cross talk, we generated an FGF18-neutralizing antibody that disrupted the stromal-leukemia feedback loop, restored CD8+ T cell effector function, and synergized with anti-PD-1 therapy to elicit durable antileukemic immunity in vivo. Collectively, these findings identify an FGF18-dependent stromal-leukemia cross talk axis that drives AML progression and immune dysfunction, highlighting FGF18 neutralization as a potential therapeutic strategy.