Acute myeloid leukemia (AML) is an aggressive bone marrow disease, characterized by increased levels of bone morphogenetic proteins (BMPs). In this study, the impact of the BMP-enriched leukemia environment was determined on surrounding cells, notably mesenchymal stem cells (MSC). BMP-2, 4, 7, 9, and TGFβ1 were presented via a biomimetic extracellular matrix to healthy and AML-MSC. We have previously shown the existence of a bidirectional cross-talk between BMP receptors and integrins, which tightly connect cell adhesion to cell differentiation. In this study, we investigated how BMPRs and integrins are regulated in the AML microenvironment, in particular in the context of MSC adhesion and differentiation. Smad phosphorylation and cell adhesive responses were assessed for MSC cultured on biomimetic materials with matrix-bound BMPs/TGFβ1 using a recently-developed high-content immunofluorescence method. The specific role of BMP receptors and of integrin beta chains in the activation of pSmad signal, cell adhesion and cell spreading was studied using silencing RNA. 33% of the AML-MSCs exhibited increased receptor levels, with higher variability for BMPR2, β1 and β5 receptors. Notably, AML-MSC exhibited an upregulated and sustained pSmad signaling, associated to ALK5, ALK6 and BMPR2 dysfunctions. AML-MSC adhesion was strongly impaired, associated with a loss of cooperation between BMPR and β integrins. Unexpectedly, β integrins inhibited AML-MSC adhesion, while BMPRI receptors promoted it, notably ALK5. Furthermore, we proved that MSCs from AML patients exhibit an impaired differentiation into osteogenic, chondrogenic and adipogenic lineage. For the first time, we proved here that MSCs present in the AML microenvironment present an altered adhesion and differentiation, due to an altered cross-talk between BMPRs and integrins. This paves the way for future therapeutic strategies taking into account ALK5 and integrin beta chains in AML disease.
Arnaldos-Pérez et al. (Wed,) studied this question.