The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells

• Non-direct crosstalk between acute myeloid leukemia cells and mesenchymal stem cells (MSCs) alters local cytokine network.
• The crosstalk also alters the global gene expression profile of the MSCs.
• Mainly affected pathways in MSCs were downstream signaling to Toll like receptors and NFκB, in addition to chemokine release.

Interactions between acute myeloid leukemia (AML) blasts and neighboring stromal cells are important for disease development and chemosensitivity. However, the molecular mechanisms involved in the cytokine-mediated crosstalk between mesenchymal stem cells (MSCs) and AML cells are largely unknown. Leukemic cells derived from 18 unselected AML patients were cultured with bone marrow MSCs derived from healthy donors; the populations then being separated by a semipermeable membrane. Coculture had only minor effects on MSC proliferation. The unique cytokine network in cocultures was determined by high constitutive MSC release of certain cytokines (especially IL-6 and vascular endothelial growth factor) and constitutive release of a wide range of soluble mediators by primary AML cells. However, the AML cell release varied considerably between patients, and these differences between patients were also reflected in the coculture levels even though supra-additive effects were seen for many mediators. These effects on the local cytokine network were dependent on a functional crosstalk between the two cell subsets. The crosstalk altered the global gene expression profile of the MSCs, especially expression of genes encoding proteins involved in downstream signaling from Toll like receptors, NFκB signaling and CCL/CXCL chemokine release. Thus, primary AML cells alter the functional phenotype of normal MSCs.