1. ¹E0217 INSERM, Université Victor SEGALEN Bordeaux 2, Hématopoïèse Leucémique et Cibles Thérapeutiques, Bordeaux cedex, France
2. ²UMR 8147 CNRS, Hôpital Necker, Paris Cedex, France
3. ³Pôle Protéomique, Plateforme Génomique Fonctionelle, Université Victor SEGALEN Bordeaux 2, Bordeaux cedex, France
4. ⁴Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK

Correspondence: Dr J-M Pasquet, E0217 INSERM, Université Victor SEGALEN Bordeaux 2, Hématopoïèse Leucémique et Cibles Thérapeutiques, 146 rue Léo Saignat, Bat 1B, Rdc, 33076 Bordeaux cedex, France. E-mail: Jean-max.pasquet@umr5533.u-bordeaux2.fr

Received 29 June 2006; Revised 28 September 2006; Accepted 2 October 2006; Published online 16 November 2006.

Abstract

Imatinib is an effective therapy for chronic myeloid leukemia (CML), a myeloproliferative disorder characterized by the expression of the recombinant oncoprotein Bcr-Abl. In this investigation, we studied an imatinib-resistant cell line (K562-r) generated from the K562 cell line in which none of the previously described mechanisms of resistance had been detected. A threefold increase in the expression of the heat-shock protein 70 (Hsp70) was detected in these cells. This increase was not associated to heat-shock transcription factor-1 (HSF-1) overexpression or activation. RNA silencing of Hsp70 decreased dramatically its expression (90%), and was accompanied by a 34% reduction in cell viability. Overexpression of Hsp70 in the imatinib-sensitive K562 line induced resistance to imatinib as detected by a large reduction in cell death in the presence of 1 M of imatinib. Hsp70 level was also increased in blast cells of CML patients resistant to imatinib, whereas the level remained low in responding patients. Taken together, the results demonstrate that overexpression of Hsp70 can lead to both in vitro and in vivo resistance to imatinib in CML cells. Moreover, the overexpression of Hsp70 detected in imatinib-resistant CML patients supports this mechanism and identifies potentially a marker and a therapeutic target of CML evolution.