The Hsp90 Inhibitor 17-allylamide-17-demethoxygeldanamycin Induces Apoptosis And Differentiation Of Kasumi-1 Harboring The Asn822Lys KIT Mutation And Down-regulates KIT Protein Level

Heat shock protein 90 (HSP90) serves as a chaperone for a number of cell signaling proteins, including many tyrosine and serine/threonine kinases, which are involved in proliferation and/or survival. The benzoquinone ansamycin geldanamycin has been shown to bind to HSP90 and to specifically inhibit this chaperone's function, resulting in client protein destabilization. 17-Allylamino-17-demethoxygeldanamycin (17AAG) is a chemical derivative of geldanamycin. KIT is the receptor for stem cell factor (SCF) and required for normal hematopoiesis. Mutations in c-kit result in ligand-independent tyrosine kinase activity and uncontrolled cell proliferation. Kasumi-1 is t(8;21) acute myeloid leukemia (AML) cell line harboring mutated KIT with Asn822Lys substitution.In order to explore the effects of HSP90 inhibitor 17AAG on AML, we have completed the following work in this study:1. The biological effects on Kasumi-1 cells of 17AAGOur present studies demonstrate that 17AAG inhibits Kasumi-1 cells proliferation and exerts apoptosis- and differentiation-inducing effects in a dose- and time-dependent manner. The growth-inhibitory IC50 value for 17AAG treatment is 0.62 umol/L. Characteristic apoptotic features were confirmed by morphology, internucleosomal DNA fragmentation, and annexin V staining. 17AAG also causes the G0/G1 block of Kasumi-1 cells.2. Study on mechanisms underlying differentiation and apoptosis of Kasumi-1 cells induced by 17AAG...