Hsp90 Expression in Acute Myeloid Leukaemia.

Heat shock protein inhibitors are a potential new class of anti-leukaemic agents with FLT-3 inhibitory activity. 17-allylamino-17-demethoxygeldanamycin (17-AAG) targets Hsp90 which functions as a molecular chaperone protein that promotes folding of nascent and stress denatured proteins helping them to achieve the correct conformation or targeting them for degradation. Hsp90 conformation is altered by binding ATP to a hydrophobic N-terminal pocket leading to hydrolysis which allows the protein to interact with a co-chaperone complex. 17-AAG fills the ATP binding pocket, displacing the nucleotide and inhibiting the function of Hsp90 as a chaperone. 17-AAG may affect signal transduction resulting from client proteins such as p53, c-Raf-1, Akt, Bcr-Abl and FLT-3. The level of expression of Hsp90 in AML is unknown. To examine the expression 252 AML cases and 9 normal samples were assessed by U133A GeneChips with the data analysed by MAS5 and GeneSpring 6.2.1 to give normalised gene expression of Hsp90α and β, a subset of which were then validated by real-time quantitative RT-PCR. The normalised expression range of Hspα was 0.132 to 2.727 with a mean of 0.982 (n=252) which was not significantly different from normal (0.876: n=9). Hsp90α expression was not significantly different in FAB groups, cytogenetic risk group, FLT-3 status overall or within cytogenetic risk groups. The expression of Hsp90β in the AML samples (n=252) (0.959: range 0.171 to 3.397) was not different from normal samples (0.944: range 0.535 to 1.095). However the APL subgroup (M3) (n=31) had a lower expression (0.722) than the other FAB groups (M0, M1, M2, M4, M5, M6, M7) p=0.029. There was no difference within other FAB subgroups. Apart from the influence of the t(15;17) subgroup expression levels did not vary significantly in the cytogenetic risk groups, or with the presence of a FLT-3 mutation overall or within cytogenetic risk groups. Conclusion: Hsp90 isoform expression in AML is variable over a 21 fold range. Expression does not correlate with FAB, cytogenetic risk group or FLT-3 mutation status. The relationship to clinical outcome is currently being analysed.