Heat Shock Protein 90 is overexpressed in high-risk myelodysplastic syndromes and associated with higher expression and activation of Focal Adhesion Kinase

Pascale Flandrin-Gresta,Nathalie Nadal,Eric Wattel,Françoise Solly,Denis Guyotat,Emmanuelle Tavernier,Carmen Mariana Aanei,Jérôme Cornillon,Franck Morteux,Lydia Campos

doi:10.18632/oncotarget.557

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.

Highlights

The myelodysplastic syndromes (MDS) are a heterogeneous group of diseases with regard to initial presentation and evolution [1]
We show that heat shock protein 90 (HSP90) and FAK are overexpressed in high risk cases, and that CD34+ cells are highly sensitive to the HSP90 inhibitor 17-allylamino-demethoxy geldanamycin (17-AAG)
We show that high expression of HSP90 is associated with increasingly advanced disease and poor clinical prognosis

Summary

Introduction

The myelodysplastic syndromes (MDS) are a heterogeneous group of diseases with regard to initial presentation and evolution [1]. Patients with MDS usually present with one or several peripheral cytopenias despite a normo- or hypercellular bone marrow (BM). This apparent paradox has been linked to an excessive intramedullary apoptosis [2,3,4], but mechanisms underlying this phenomenon are not fully understood yet. Increased apoptosis is observed in all forms of MDS, but is higher in patients with better prognosis and comparatively lower in patients with an excess of blasts [5,6]

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