title: Heat Shock Protein 90 is overexpressed in high-risk myelodysplastic syndromes and associated with higher expression and activation of Focal Adhesion Kinase.
abstract: Myelodysplastic syndromes are characterized by a high risk of evolution into acute myeloid leukaemia which can involve activation of signalling pathways. As the chaperone heat shock protein 90 (HSP90) has a key role in signal transduction, we investigated its role in the pathogenesis and evolution of myelodysplastic syndromes. Expressions of HSP90 and signalling proteins clients (phosphorylated-AKT (pAKT), Focal Adhesion Kinase (FAK) and phosphorylated-FAK (pFAK)), were assessed in bone marrow mononuclear and CD34-positive (CD34+) cells from 177 patients with myelodysplasia. Effects of HSP90 inhibition were also evaluated in 39 samples. The levels of all proteins studied were significantly higher in patients with high grade disease, than those with low grade myelodysplastic syndrome or chronic myelomonocytic leukaemia. High levels of HSP90, FAK, pFAK and pAKT were associated with shorter survival and increased risk of progression into acute leukaemia. A down regulation of pFAK and pAKT and increased apoptosis was observed in mononuclear and CD34+ cells after 12 hours of incubation with 17-AAG. In conclusion, our data suggest the implication of HSP90 and FAK and AKT activation in the pathogenesis of myelodysplastic syndromes with excess of blasts and evolution to leukaemia. Moreover this signalling network could be a therapeutic target through HSP90 inhibition.
authors.affiliation: Laboratoire d'Hématologie, University Hospital of Saint-Etienne, University Hospital of Saint-Etienne, 42055 Saint-Etienne Cedex 2, France.pascale.flandrin-gresta@chu-st-etienne.fr
authors.forename: Pascale
authors.initials: P
authors.lastname: Flandrin-Gresta
authors.forename: Françoise
authors.initials: F
authors.lastname: Solly
authors.forename: Carmen Mariana
authors.initials: CM
authors.lastname: Aanei
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cornillon
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tavernier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nadal
authors.forename: Franck
authors.initials: F
authors.lastname: Morteux
authors.forename: Denis
authors.initials: D
authors.lastname: Guyotat
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
authors.forename: Lydia
authors.initials: L
authors.lastname: Campos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016227:Benzoquinones / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D002648:Child; D005260:Female; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D005500:Follow-Up Studies; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt