• Stroma cells promote induction of a S100A8/A9high AML cell subset via IL-6/Jak/STAT3 signaling

  • S100A8/A9high AML cells display a distinct metabolic, differentiation, and chemoresistance profile

The bone marrow (BM) stroma represents a protective niche for acute myeloid leukemia (AML) cells. However, the complex underlying mechanisms remain to be fully elucidated. We found 2 small intracellular calcium-sensing molecules, S100A8 and S100A9, among the top genes being upregulated in primary AML blasts upon stromal contact. As members of the S100 protein family they can modulate cellular processes like proliferation, migration, and differentiation. Dysregulation of S100 proteins is described in different human cancers including increased S100A8 expression in de novo AML as a predictor of poor survival. Thus, we aimed to decipher the underlying pathways of stroma-mediated S100A8/A9 induction as well as its functional consequences. Upregulation of S100A8/A9 following stromal crosstalk was validated in AML cell lines, was contact-independent and reversible, and resulted in accumulation of S100A8/A9highcells. Accordingly, frequency of S100A8/A9high AML blasts was higher in the patients' BM as compared to peripheral blood. This S100A8/A9high AML cell population displayed an enhanced utilization of free fatty acids, features of a more mature myeloid phenotype, and increased resilience towards chemotherapeutics and BCL2 inhibition. We could identify stromal cell-derived interleukin-6 (IL-6) as the trigger for a Jak/STAT3 signaling-mediated S100A8/A9 induction. Interfering with fatty acid uptake and the IL-6-Jak/STAT3 pathway antagonized formation of S100A8/A9high cells and therapeutic resistance, which could have therapeutic implications as a strategy to interfere with the AML-niche dynamics

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