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Acute Promyelocytic Leukemia

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

Leukemia volumeĀ 15,Ā pages 1176ā€“1184 (2001)Cite this article

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/RARĪ± 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.

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Acknowledgements

This work was supported by grants from the Ministry of Education, Science and Culture in Japan, and by a National Grant-in-Aid for the Establishment of a High-Tech Research Center in a Private University.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology, Keio University School of Medicine, Tokyo, Japan

    A Muto,Ā M Kizaki,Ā C Kawamura,Ā H Matsushita,Ā Y FukuchiĀ &Ā Y Ikeda

  2. Department of Pathology, Division of Hematology, Keio University School of Medicine, Tokyo, Japan

    A Umezawa,Ā T YamadaĀ &Ā J Hata

  3. Institute of Biological Science, Science University of Tokyo, Chiba, Japan

    N Hozumi

  4. Department of Oral Function Restitution, Division of Oral Health Sciences, Section of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University, Tokyo, Japan

    K Yamato

  5. Central Institute for Experimental Animals, Kanagawa

    M Ito

  6. Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan

    Y Ueyama

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Muto, A., Kizaki, M., Kawamura, C. et al. A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF. Leukemia 15, 1176ā€“1184 (2001). https://doi.org/10.1038/sj.leu.2402162

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