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

Shinya Rai, Hirokazu Tanaka (), Mai Suzuki, J. Luis Espinoza, Takahiro Kumode, Akira Tanimura, Takafumi Yokota, Kenji Oritani, Toshio Watanabe, Yuzuru Kanakura and Itaru Matsumura
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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

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17666-8

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