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Synergistic Effect of Arsenic Trioxide and Flt3 Inhibition on Cells with Flt3 Internal Tandem Duplication

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Abstract

Flt3 internal tandem duplication (Flt3-ITD) is a prevalent mutation in acute myeloid leukemia (AML). Flt3-ITD constitutively activates various signaling pathways, including a mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Arsenic trioxide (ATO) and MEK inhibition were recently reported to interact synergistically to induce apoptosis in AML cells. In this study, we aimed to clarify whether ATO and Flt3 inhibition would be a mor specific and efficient therapy for Flt3-ITD cells.We demonstrate that the combination of ATO and an Flt3 inhibitor,AG1296, profoundly inhibits the growth of Flt3-ITD cells and induces their apoptosis. We further revealed that this combined treatment potently inhibits the ERK activity that might be responsible for cell growth. Moreover, using the Chou-Talalay method, we observed a synergistic growth-inhibitory effect for ATO and AG1296 in Flt3-ITD cells (BaF3-Flt3-ITD, MV4-11, and PL-21 cells), but not in Flt3 wild-type cells (RS4-11 and NB4 cells), for almost all dose ranges tested. Our results provide an experimental basis for a specific and efficient therapy for Flt3-ITD cells that involves combined treatment with Flt3 inhibitors and ATO.

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Authors and Affiliations

  1. Departments of Infection Control and Laboratory Diagnostics, Tohoku University Graduate School of Medicine, 1-1, Seiryou-machi, Aobaku, 980-8574, Sendai, Japan

    Shinichiro Takahashi & Mitsuo Kaku

  2. Department of Rheumatology and Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Hideo Harigae, Hisayuki Yokoyama & Takeshi Sasaki

  3. Department of Internal Medicine, Osaki Citizen Hospital, Osaki, Japan

    Izumi Ishikawa & Shouri Abe

  4. Department of Hematology and Oncology, Miyagi Children’s Hospital, Sendai, Japan

    Masue Imaizumi

Authors
  1. Shinichiro Takahashi
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  2. Hideo Harigae
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  3. Hisayuki Yokoyama
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  4. Izumi Ishikawa
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  5. Shouri Abe
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  6. Masue Imaizumi
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  7. Takeshi Sasaki
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  8. Mitsuo Kaku
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Correspondence to Shinichiro Takahashi.

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Takahashi, S., Harigae, H., Yokoyama, H. et al. Synergistic Effect of Arsenic Trioxide and Flt3 Inhibition on Cells with Flt3 Internal Tandem Duplication. Int J Hematol 84, 256–261 (2006). https://doi.org/10.1532/IJH97.06076

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  • DOI: https://doi.org/10.1532/IJH97.06076

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