Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V
| Autor: | Mai Suzuki, J. Luis Espinoza, Yuzuru Kanakura, Itaru Matsumura, Kenji Oritani, Shinya Rai, Takafumi Yokota, Akira Tanimura, Toshio Watanabe, Takahiro Kumode, Hirokazu Tanaka |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Myeloid General Physics and Astronomy Apoptosis 02 engineering and technology CD38 Receptor tyrosine kinase Mice hemic and lymphatic diseases lcsh:Science Aged 80 and over Mice Inbred BALB C Multidisciplinary biology Chemistry Cancer stem cells Myeloid leukemia Middle Aged 021001 nanoscience & nanotechnology Endocytosis Leukemia Leukemia Myeloid Acute Proto-Oncogene Proteins c-kit medicine.anatomical_structure Tandem Repeat Sequences Monomeric Clathrin Assembly Proteins embryonic structures Female 0210 nano-technology Signal Transduction Adult animal structures Adolescent Cell Survival Chlorpromazine Science Transplantation Heterologous Mice Nude Antineoplastic Agents HL-60 Cells General Biochemistry Genetics and Molecular Biology Article Acute myeloid leukaemia 03 medical and health sciences Young Adult Cancer stem cell medicine Animals Humans Point Mutation neoplasms Aged Cell Proliferation Cell growth Growth factor signalling General Chemistry Translational research medicine.disease Transplantation 030104 developmental biology fms-Like Tyrosine Kinase 3 Cancer research biology.protein lcsh:Q |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) |
| ISSN: | 2041-1723 |
| Popis: | 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. Receptor tyrosine kinase mutations are frequent and associated with poor prognosis in acute myeloid leukemia (AML). Here the authors show that the antipsychotic drug chlorpromazine reduces AML cells viability by perturbing the intracellular localization of FLT3-ITD and KIT-D816V. |
| Databáze: | OpenAIRE |
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