Combined Arsenic Trioxide and GM-CSF Induces Differentiation in Retinoic Acid (RA)-Sensitive as well as -Resistant APL Cells by Modulating Jak2 Kinase

Summary

Arsenic trioxide (As₂0₃) is effective for the patients with relapsed acute promyelocytic leukemia (APL); however, possible adverse effects of this new anti-leukemic drug are highly important issue related to its clinical use. To resolve this problem, we here investigated in vitro and in vivo, the effects of the combination of AS₂0₃ and GM-CSF as a novel therapeutic approach for the treatment of APL. Treatment of both retinoic acid (RA)-sensi- tive and -resistant APL cell lines (NB4 and UF-1 cells, respectively) with the combination of AS₂0₃ and GM-CSF for 4 days resulted in inducing differentiation, but not apoptosis, to mature granulocytes. In addition, the combination of both agents induced degradation of PML/RARα protein. While GM-CSF did not affect the expression of Bcl-2, it decreased the levels of Bax protein in As₂0₃-treated cells. In addition, both chemicals increased the levels of Mcl-1 in APL cells. A specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of As₂0₃-treated UF-1 cells. In in vivo analysis, As₂0₃ decreased the size of tumors in an RA-resistant APL model of human GM-CSF-producing transgenic SCID mice that had a high level of human GM-CSF in their sera. Moreover, diminished tumors showed mature granulocytes, indicating that As₂0₃ in combination with GM-CSF also induced differentiation of APL cells in vivo. In conclusion, the combination of As₂0₃ and GM-CSF would be a novel differentiation- inducing therapy in patients with APL.