Significance of heat-shock protein (HSP) 90 expression in acute myeloid leukemia cells.
The 90-kDa heat shock protein (HSP90) is implicated in the conformational maturation and stabilization of a variety of client proteins with receptor and signal transduction functions. The objective of this study was to assess its expression in primary acute myeloid leukemia (AML) cells and to evaluate its biological and clinical significance. The in vitro effects of 17-AAG, a selective inhibitor of HSP90, was also evaluated. Cells from 65 patients with newly diagnosed AML were studied. The expression of HSP90 correlated with that of CD34, p170, and bcl-2 proteins but not with white cell counts, FAB or WHO subtype, or cytogenetics. HSP90 levels were also higher in samples exhibiting an autonomous growth in liquid culture or forming spontaneous colonies. A concomitant constitutive activation of the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/AKT pathways was observed in a majority of samples and was significantly correlated with HSP90 expression. All patients received induction chemotherapy. The percentages of HSP90-, CD34-, bcl-2-, and p170-positive cells were higher in patients who did not attain complete remission. Survival was also shorter in patients with high levels of HSP90. In vitro exposure of leukemic cells to 17-allylamino-demethoxy geldanamycin (17-AAG) resulted in inhibition of growth in liquid and clonogeneic cultures and in apoptosis, at concentrations which in most cases were not toxic for normal CD34-positive or progenitor cells. The concentration inhibiting 50% growth at 72 h in liquid culture correlated with HSP90 expression. Our study suggests that HSP90 is overexpressed in poor-prognosis AML cells and plays a role in cell survival and resistance to chemotherapy. Targeted therapy with 17-AAG represents a promising antileukemic strategy in adult AML.
Flandrin
Pascale
P
Laboratoire d'Hématologie, Hôpital Nord, CHU de Saint-Etienne, Saint-Etienne Cedex 02, France. pascale.flandrin-gresta@chu-st-etienne.fr
Guyotat
Denis
D
Duval
Amélie
A
Cornillon
Jérôme
J
Tavernier
Emmanuelle
E
Nadal
Nathalie
N
Campos
Lydia
L
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013223:Statistics as Topic; D015996:Survival Rate
D018952:Antigens, CD34; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin