A Pilot Study On Effects And Mechanisms Of Action Of Proteasome Inhibitors On T(8;21) Leukemia

Acute myeloid leukemia (AML) is a heterogenous group of hematopoietic malignancies. Significant advances in understanding the cytogenetic and molecular aspects of , as well as the signal transdution pathway involved in, this malignancy have been achieved in the past 20 years.Meanwhile, substantial progress has also been made in the treatment of patients with AML.However, most patients remain incurable. Hence development of new drugs for treatment of AML is of at most importance.We found that Rabdocoetsin B (Rabd-B), a diterpenoid extracted from Isodon coetsa is a potential proteasome inhibitor which induces programmed cell death of t(8;21) cells.Rabd-B induced growth inhibition and apoptosis of Kasumi-1 cells in a dose-dependent manner. The cleavage of S6'and the accumulation of ubiquitinated proteins were found in Kasumi-1 cells treated with Rabd-B. Further study may provide evidence for employing Rabd-B in treating human t(8;21) leukemia.Besides, we reported that PS-341 triggered a caspase-dependent degradation of AML1-ETO(AE) with generation of a 70 kD catalytic fragment, which served as a dominant negative form of the full-length AE and facilitated apoptosis of t(8;21) cells. AE oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations, while AE9a alone induces leukemia in animal models. PS-341 also caused degradation of AE9a and showed significant anti-leukemia efficacies in murine models, suggesting a clinically available AE-targeting agent for t(8;21) leukemia. With the molecular mechanism study of the targeted therapy for hematopoietic malignancies, we propose to establish the basis for developing more effective therapeutic and optimizing the treatment further.