Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells

Direct cell-cell contact between haematopoietic progenitor cells (HPCs) and their cellular microenvironment is essential to maintain 'stemness'. In cancer biology, focal adhesion (FA) proteins are involved in survival signal transduction in a wide variety of human tumours. To define the role of FA proteins in the haematopoietic microenvironment of myelodysplastic syndromes (MDS), CD73-positive mesenchymal stromal cells (MSCs) were immunostained for paxillin, pFAK [Y-397], and HSP90 alpha/beta and p130CAS, and analysed for reactivity, intensity and cellular localisation. Immunofluorescence microscopy allowed us to identify qualitative and quantitative differences, and subcellular localisation analysis revealed that in pathological MSCs, paxillin, pFAK [Y-397], and HSP90 alpha/beta formed nuclear molecular complexes. Increased expression of paxillin, pFAK [Y-397], and HSP90 alpha/beta and enhanced nuclear co-localisation of these proteins correlated with a consistent proliferative advantage in MSCs from patients with refractory anaemia with excess blasts (RAEB) and negatively impacted clonogenicity of HPCs. These results suggest that signalling via FA proteins could be implicated in HPC-MSC interactions. Further, because FAK is an HSP90 alpha/beta client protein, these results suggest the utility of HSP90 alpha/beta inhibition as a target for adjuvant therapy for myelodysplasia. (C) 2011 Elsevier Inc. All rights reserved.