Establishment of novel differentiation-inducing therapy for leukemia with hematopoietic growth factors and arsenic trioxide

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Arsenic trioxide (As_2O_3) effectively induces clinical remission via apoptosis in related acute promyelocytic leukemia (APL). However, because this new anti-leukemic drug is also considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. We investigated both in vitro and in vivo, the effects of a combination of As_2O_3 and GM-CSF as a novel therapeutic approach for the treatment of acute leukemia. Treatment of acute lmyeloid eukemic cells with a combination of As_2O_3 and GM-CSF for 4 days resulted in differentiation, but not apoptosis, to mature granulocytes. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in acute promyelocytic leukemia (APL) cells, and a specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of As_2O_3-treated APL cells. In in vivo analysis, As_2O_3 induced differentiation of APL cells in a retinoic aci … More d-resistant APL model of human GM-CSF-producing transgenic SCID mice that had a high level of human GM-CSF in their sera. In contrast, As_2O_3 alone diminished tumors in retinoic acid-resistant APL UF-1 cells transplanted into NOD/SCID mice via induction of apoptosis.We also performed the experiments using TGF-β superfamily cytokines including bone morphogenetic protein(BMP) and activin A for inducing apoptosis of leukemia and myeloma cells. BMP induces apoptosis of human myeloma cell lines and primary samples. BMP caused cell cycle arrest in the G1 phase which was associated with accumulation of p21 and p27, and the subsequent apoptosis of myeloma cells. BMP also induced down-regulation of Bcl-X_L through the inactivation of STAT3, resulting in the induction of apoptosis of myeloma cells. In addition, activin A induced rapid apoptosis of chronic myeloid leukemia (CML) cells via transient induction of Mcl-1. These results suggest that cytokines may have a potential to be novel therapeutic agents for treatment in patients with leukemia and myeloma. Especially, a combination of As_2O_3 and GM-CSF appears to be a novel differentiation-inducing therapy for APL with less toxic effects. Less