Significance of heat-shock protein (HSP) 90 expression in acute myeloid leukemia cells

Abstract

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.

Functional characterization of high levels of meningioma 1 as collaborating oncogene in acute leukemia

“…27,28 Interestingly, several genes flanking the integration sites, such as SOCS1, JARID2, PTPRE, HSP90, GADD45, MGAT5, PP2R5C or MN1, have been previously linked to carcinogenesis (Table 1). [29][30][31][32][33] The integration near the MN1 locus resulted in significantly increased levels of mRNA expression (Figure 1a). Interestingly, the MN1 gene locus has been previously reported as a recurrent integration site in mouse models of human hematological malignancies induced by retroviral oncogene expression such as NUP98-HOXD13 or mutated AML1.…”

Hsp90α forms a stable complex at cilia neck for signal molecules interaction in cilia-mediated IGF-1 receptor signaling

“…Hsp90 is a conserved molecular chaperone that targets specific client proteins involved in signal transduction, protein refolding, protein degradation, etc. (Pratt and Toft, 2003;Flandrin et al, 2008;Zhao et al, 2005;Jackson, 2013). For example, it has been reported that Hsp90 can bind to Akt to protect it from phosphatase 2A (PP2A)-catalysed dephosphorylation and to regulate the kinase activity (Sato et al, 2000;Basso et al, 2002).…”

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

“…[1][2][3] Extensive preclinical studies have examined this chaperone as a potential new drug target in hematologic malignancies. [3][4][5][6][7] Among the more than 80 currently identified Hsp90 client proteins there are several kinases involved in myeloid neoplasms, including Bcr/abl, 8,9 Flt3, 4,10,11 and c-Kit, 12 as well as the anti-apoptotic kinase Akt. 13,14 When Hsp90 is inhibited, these polypeptides and other Hsp90 clients fail to fold properly during synthesis and, as a consequence, become less abundant as mature molecules turn over.…”