Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V.
Shinya RaiHirokazu TanakaMai SuzukiJ Luis EspinozaTakahiro KumodeAkira TanimuraTakafumi YokotaKenji OritaniToshio WatanabeYuzuru KanakuraItaru MatsumuraPublished in: Nature communications (2020)
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.
Keyphrases
- acute myeloid leukemia
- tyrosine kinase
- induced apoptosis
- allogeneic hematopoietic stem cell transplantation
- cell cycle arrest
- wild type
- signaling pathway
- epidermal growth factor receptor
- endoplasmic reticulum stress
- emergency department
- oxidative stress
- cell death
- amino acid
- bone marrow
- immune response
- drug induced
- heat shock protein
- heat shock
- adverse drug