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.
Highlights
Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMSlike tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid leukemia (AML)
These results suggest that Clathrin assembly lymphoid myeloid leukemia protein (CALM) and/or its associate proteins would somewhat differently regulate the trafficking of MT-RTKs and that of WT-RTKs
In accord with previous reports, we found that Fms-like tyrosine kinase 3 (FLT3) ITD is predominantly localized at endoplasmic reticulum (ER) and KIT D816V at endolysosomes, where they activate themselves and their downstream molecules, STAT5 and Akt
Summary
Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMSlike tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid leukemia (AML). Consistent with this observation, the amount of FLT3 ITD was severely reduced by CALM iKD or CPZ treatment in the isolated PDI-positive ER fraction compared with untreated cells (Fig. 5a).
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