title: 2-(trimethylammonium)ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate promotes megakaryocytic differentiation of myeloid leukaemia cells and primary human CD34⁺ haematopoietic stem cells.
abstract: In this study we showed that 2-(trimethylammonium)ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient differentiation of megakaryocytes. Specifically, (R)-TEMOSPho induces cell cycle arrest, cell size increase and polyploidization from K562 and HEL cells, which are used extensively to model megakaryocytic differentiation. In addition, megakaryocyte-specific cell surface markers showed a dramatic increase in expression in response to (R)-TEMOSPho treatment. Importantly, we demonstrated that such megakaryocytic differentiation can also be induced from primary human CD34(+) haematopoietic stem cells. Activation of the PI3K-AKT pathway and, to a lesser extent, the MEK-ERK pathway appears to be required for this process, as blocking with specific inhibitors interferes with the differentiation of K562 cells. A subset of (R)-TEMOSPho-treated K562 cells undergoes spontaneous apoptosis and produces platelets that are apparently functional, as they bind to fibrinogen, express P-selectin and aggregate in response to SFLLRN and AYPGFK, the activating peptides for the PAR1 and PAR4 receptors, respectively. Taken together, these results indicate that (R)-TEMOSPho will be useful for dissecting the molecular mechanisms of megakaryocytic differentiation, and that this class of compounds represents potential therapeutic reagents for thrombocytopenia.
authors.affiliation: Division of Life and Pharmaceutical Sciences and Centre for Cell Signalling and Drug Discovery Research, Ewha Womans University, Seoul, Republic of Korea; Department of Chemistry and Division of Nano Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jin-Kyung
authors.initials: JK
authors.lastname: Limb
authors.forename: Doona
authors.initials: D
authors.lastname: Song
authors.forename: Mijeong
authors.initials: M
authors.lastname: Jeon
authors.forename: So-Yeop
authors.initials: SY
authors.lastname: Han
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
authors.forename: Gil-Ja
authors.initials: GJ
authors.lastname: Jhon
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
authors.forename: Jaesang
authors.initials: J
authors.lastname: Kim
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008533:Megakaryocytes / Q000378:metabolism*; D010755:Organophosphates / Q000494:pharmacology*; D019007:P-Selectin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D018179:Receptors, Thrombin / Q000378:metabolism
chemical_list: C000598171:2-(trimethylammonium)ethyl 3-methoxy-3-oxo-2-stearamidopropyl phosphate; D010755:Organophosphates; D019007:P-Selectin; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C112908:protease-activated receptor 4