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Expression profile of heat shock proteins in acute myeloid leukaemia patients reveals a distinct signature strongly associated with FLT3 mutation status – consequences and potentials for pharmacological intervention
Author(s) -
Reikvam Håkon,
Hatfield Kimberley J.,
Ersvær Elisabeth,
Hovland Randi,
Skavland Jørn,
Gjertsen Bjørn T.,
Petersen Kjell,
Bruserud Øystein
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2011.08960.x
Subject(s) - hsp90 , heat shock protein , hsp90 inhibitor , biology , cancer research , cytokine , hsp70 , haematopoiesis , immunology , microbiology and biotechnology , gene , genetics , stem cell
Summary Heat shock proteins (HSPs) are molecular chaperones that assist proteins in their folding to native structures. HSPs are regarded as possible therapeutic targets in acute myeloid leukaemia (AML). We used bioinformatical approaches to characterize the HSP profile in AML cells from 75 consecutive patients, in addition to the effect of the HSP90 inhibitor 17‐DMAG. Patients harbouring a FLT3 ‐internal tandem duplication ( FLT3 ‐ITD) were extensively overrepresented in the cluster with high HSP levels, indicating a strong dependence of HSPs in stabilizing FLT3 ‐ITD encoded oncoproteins. FLT3 ligation further increased the levels of HSP90 and its co‐chaperone HSP70. HSP90 inhibition had a stronger pro‐apoptotic effect for AML cells with FLT3 ‐ITD than for cells with wild‐type FLT3 , whereas the anti‐proliferative effect of HSP90 inhibition was similar for the two patient subsets. HSP90 inhibition altered the constitutive cytokine release profile in an anti‐angiogenic direction independent of FLT3 mutational status: (i) pro‐angiogenic CXCL8, MMP‐2 and MMP‐9 showed a stronger decrease than anti‐angiogenic CXCL9–11, (ii) the Tie‐2 agonist Ang‐1 showed a stronger decrease than the potentially antagonistic Ang‐2, and (iii) VEGF and HGF levels were decreased. Finally, HSP90 inhibition counteracted the leukaemia‐stimulating effect of endothelial cells. Our studies demonstrate that HSP90 inhibition mediates anti‐leukaemic effects through both direct and indirect activity.