title: Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells.
abstract: 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 HSP90α/β 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 HSP90α/β formed nuclear molecular complexes. Increased expression of paxillin, pFAK [Y(397)], and HSP90α/β 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 HSP90α/β client protein, these results suggest the utility of HSP90α/β inhibition as a target for adjuvant therapy for myelodysplasia.
authors.affiliation: Laboratoire Hématologie, CHU de Saint-Etienne, 42055 Saint-Etienne, France. caanei@yahoo.com
authors.forename: Carmen Mariana
authors.initials: CM
authors.lastname: Aanei
authors.forename: Florin Zugun
authors.initials: FZ
authors.lastname: Eloae
authors.forename: Pascale
authors.initials: P
authors.lastname: Flandrin-Gresta
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tavernier
authors.forename: Eugen
authors.initials: E
authors.lastname: Carasevici
authors.forename: Denis
authors.initials: D
authors.lastname: Guyotat
authors.forename: Lydia
authors.initials: L
authors.lastname: Campos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism* / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology; D051419:Paxillin / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D018841:HSP90 Heat-Shock Proteins; D051419:Paxillin; D051416:Focal Adhesion Protein-Tyrosine Kinases