Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia.
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 muM 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.
Pocaly
M
M
E0217 INSERM, Université Victor SEGALEN Bordeaux 2, Hématopoïèse Leucémique et Cibles Thérapeutiques, Bordeaux cedex, France.
Lagarde
V
V
Etienne
G
G
Ribeil
J-A
JA
Claverol
S
S
Bonneu
M
M
Moreau-Gaudry
F
F
Guyonnet-Duperat
V
V
Hermine
O
O
Melo
J V
JV
Dupouy
M
M
Turcq
B
B
Mahon
F-X
FX
Pasquet
J-M
JM
D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D018840:HSP70 Heat-Shock Proteins; D016044:Fusion Proteins, bcr-abl