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Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V

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Listed:
  • Shinya Rai

    (Kindai University Faculty of Medicine)

  • Hirokazu Tanaka

    (Kindai University Faculty of Medicine)

  • Mai Suzuki

    (National Cancer Center Research Institute)

  • J. Luis Espinoza

    (Kindai University Faculty of Medicine)

  • Takahiro Kumode

    (Kindai University Faculty of Medicine)

  • Akira Tanimura

    (Osaka University Graduate School of Medicine)

  • Takafumi Yokota

    (Osaka University Graduate School of Medicine)

  • Kenji Oritani

    (International University of Health and Welfare)

  • Toshio Watanabe

    (Graduate School of Humanities and Sciences, Nara Women’s University)

  • Yuzuru Kanakura

    (Osaka University Graduate School of Medicine)

  • Itaru Matsumura

    (Kindai University Faculty of Medicine)

Abstract

Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid leukemia (AML). Clathrin assembly lymphoid myeloid leukemia protein (CALM) regulates intracellular transport of RTKs, however, the precise role for MT-RTKs remains elusive. We here show that CALM knock down leads to severely impaired FLT3 ITD- or KIT D814V-dependent cell growth compared to marginal influence on wild-type FLT3- or KIT-mediated cell growth. An antipsychotic drug chlorpromazine (CPZ) suppresses the growth of primary AML samples, and human CD34+CD38- AML cells including AML initiating cells with MT-RTKs in vitro and in vivo. Mechanistically, CPZ reduces CALM protein at post transcriptional level and perturbs the intracellular localization of MT-RTKs, thereby blocking their signaling. Our study presents a therapeutic strategy for AML with MT-RTKs by altering the intracellular localization of MT-RTKs using CPZ.

Suggested Citation

  • Shinya Rai & Hirokazu Tanaka & Mai Suzuki & J. Luis Espinoza & Takahiro Kumode & Akira Tanimura & Takafumi Yokota & Kenji Oritani & Toshio Watanabe & Yuzuru Kanakura & Itaru Matsumura, 2020. "Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17666-8
    DOI: 10.1038/s41467-020-17666-8
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