Abstract
Arsenic is an ancient drug, used for many centuries to treat a broad range of ailments including cancer but was largely abandoned in the early 20th century. In the 1990s arsenic trioxide (ATO) was rediscovered as an effective treatment for patients suffering from acute promyelocytic leukemia (APL). ATO has been shown to specifically target the fusion protein resulting from the t(15;17) translocation, PML/RARα, and subsequently stimulate differentiation and apoptosis of APL cells both in vitro and in vivo. The success in using ATO as a targeted therapy for APL underscores the importance of matching the right drug to patients with appropriate molecular targets. We previously reported that expression of the AML1/MDS1/EVI1 (AME) transcription factor fusion protein [a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of chronic myelogenous leukemia during the blast phase and in some patients with de novo and therapy-related myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML)] in mouse bone marrow cells by retroviral transduction impaired hematopoiesis and eventually induced an AML in mice. Our results established a causal role of AME in t(3;21)-positive myeloid malignancies. We went on to examine whether ATO could target AME. We found that ATO treatment downregulated forced-expressed AME protein in Bosc23 (a cell line derived from human 293 kidney cell line) and BM6-4 cells, a primary myeloid blast cell line derived from bone marrow of a mouse with AME-induced AML, in a dose dependent manner (within therapeutic relevant dosage range). We also found that ATO inhibited proliferation of BM6-4 cells, induced these cells to differentiate into macrophages and induced apoptosis in a dose dependent manner. Our results suggest that ATO could be used as a targeted therapy for t(3;21)-positive MDS and AML. The in vivo effect of ATO in the AME mouse model and mechanism of ATO-induced AME downregulation is under investigation. Such research may extend ATO therapy to other hematological malignancies and help to identify new therapeutic targets for human cancer.