Oncotarget

Research Papers:

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 _, Francoise Solly, Carmen Mariana Aanei, Jerome Cornillon, Emmanuelle Tavernier, Nathalie Nadal, Franck Morteux, Denis Guyotat, Eric Wattel and Lydia Campos

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Oncotarget. 2012; 3:1158-1168. https://doi.org/10.18632/oncotarget.557

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Abstract

Pascale Flandrin-Gresta1,2, Françoise Solly1,2, Carmen Mariana Aanei1, Jérôme Cornillon3, Emmanuelle Tavernier2,3, Nathalie Nadal1, Franck Morteux2, Denis Guyotat2,3, Eric Wattel2, Lydia Campos1,2,

1 Laboratoire d’Hématologie, University Hospital of Saint-Etienne, University Hospital of Saint-Etienne, 42055 Saint-Etienne Cedex 2, France.

2 UMR5239 CNRS, Université Claude Bernard Lyon 1, Faculté deMédecine J Lisfranc Saint-Etienne, 42023 Saint-Etienne Cedex 2, France.

3 Institut de Cancérologie de la Loire, University Hospital of Saint-Etienne, 42271 Saint Priesten Jarez cedex, France.

Correspondence:

Pascale Flandrin-Gresta, email:

Keywords: HSP90, MDS, FAK, 17-AAG

Received: July 18, 2012, Accepted: September 25, 2012, Published: September 28, 2012

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.


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