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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Aged, 80 and over
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Proliferation / drug effects*
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Cell Proliferation / genetics
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Cell Survival / drug effects
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Cell Survival / genetics
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Chlorpromazine / pharmacology*
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Female
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HL-60 Cells
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Middle Aged
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Monomeric Clathrin Assembly Proteins / genetics
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Monomeric Clathrin Assembly Proteins / metabolism*
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Point Mutation
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Proto-Oncogene Proteins c-kit / genetics*
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Signal Transduction / drug effects
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Tandem Repeat Sequences / genetics
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Transplantation, Heterologous
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Young Adult
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fms-Like Tyrosine Kinase 3 / genetics*
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fms-Like Tyrosine Kinase 3 / metabolism*
Substances
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Antineoplastic Agents
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Monomeric Clathrin Assembly Proteins
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PICALM protein, human
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FLT3 protein, human
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Proto-Oncogene Proteins c-kit
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fms-Like Tyrosine Kinase 3
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Chlorpromazine