A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF

作者：Muto A; Kizaki M^*; Kawamura C; Matsushita H; Fukuchi Y; Umezawa A; Yamada T; Hata J; Hozumi N; Yamato K; Ito M; Ueyama Y; Ikeda Y

来源：Leukemia, 2001, 15(8): 1176-1184.

DOI：10.1038/sj.leu.2402162

• acute promyelocytic leukemia (APL)
• arsenic trioxide
• GM-CSF
• apoptosis
• differentiation

Arsenic trioxide (As2O3) effectively induces clinical remission via apoptosis in relapsed 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 here investigated, both in vitro and in vivo, the effects of a combination of As2O3 and GM-CSF as a novel therapeutic approach for the treatment of APL. Treatment of both retinoic acid (RA)-sensitive and -resistant APL cell lines (NB4 and UF-1 cells, respectively), as well as primary APL cells with a combination of As2O3 and GMCSF for 4 days resulted in inducing differentiation, but not apoptosis, to mature granulocytes. In addition, a combination of both agents induced degradation of the PML/RAR alpha protein. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in both NB4 and UF-1 cells, and a specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of AS(2)O(3)-treated UF-1 cells. In in vivo analysis, AS(2)O(3) induced differentiation of APL cells in a RA-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(2)O(3) alone diminished tumors in UF-1 cells transplanted into NOD/SCID mice via induction of apoptosis. In conclusion, a combination of As2O3 and GM-CSF appears to be a novel differentiation-Inducing therapy in patients with APL, including relapsed or RA-resistant cases.

• 出版日期2001-8