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

A. Muto, M. Kizaki, C. Kawamura, H. Matsushita, Y. Fukuchi, A. Umezawa, T. Yamada, J. Hata, N. Hozumi, K. Yamato, M. Ito, Y. Ueyama, Y. Ikeda

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34 Citations (Scopus)

Abstract

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 GM-CSF 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/RARα 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 As2O3-treated UF-1 cells. In in vivo analysis, As2O3 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, As2O3 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.

Original languageEnglish
Pages (from-to)1176-1184
Number of pages9
JournalLeukemia
Volume15
Issue number8
DOIs
Publication statusPublished - 2001 Jan 1

Keywords

  • Acute promyelocytic leukemia (APL)
  • Apoptosis
  • Arsenic trioxide
  • Differentiation
  • GM-CSF

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    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. (2001). A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF. Leukemia, 15(8), 1176-1184. https://doi.org/10.1038/sj.leu.2402162