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Only a small proportion of HE cases are clonal malignancies, and one of these, the group of eosinophilia\u2010associated tyrosine kinase fusion\u2010driven neoplasms, is sensitive to tyrosine kinase inhibitors, while most subtypes lack specific treatment. Eosinophil functions are highly dependent on actin polymerization, promoting priming, shape change, and infiltration of inflamed tissues. Therefore, we investigated the role of the actin\u2010binding protein lymphocyte cytosolic protein 1 (LCP1) in malignant and nonmalignant eosinophil differentiation. We use the protein kinase C\u2010\u03b2 (PKC\u03b2) selective inhibitor enzastaurin (Enza) to dephosphorylate and inactivate LCP1 in FIP1L1\u2010platelet\u2010derived growth factor receptor \u03b1 (PDGFRA)\u2010positive Eol\u20101 cells, and this was associated with reduced proliferation, metabolic activity, and colony formation as well as enhanced apoptosis and impaired migration. While Enza did not alter FIP1L1\u2010PDGFRA\u2010induced signal transducer and activator of transcription 3 (STAT3), STAT5, and ERK1\/2 phosphorylation, it inhibited STAT1<jats:sup>Tyr701<\/jats:sup> and AKT<jats:sup>Ser473<\/jats:sup> (but not AKT<jats:sup>Thr308<\/jats:sup>) phosphorylation, and short hairpin RNA knockdown experiments confirmed that this process was mediated by LCP1 and associated mammalian target of rapamycin complex 2 (mTORC2) activity loss. Homeobox protein HoxB8 immortalized murine bone marrow cells showed impaired eosinophilic differentiation upon Enza treatment or LCP1 knockdown. Furthermore, Enza treatment of primary HE samples reduced eosinophil differentiation and survival. In conclusion, our data show that HE involves active LCP1, which interacts with mTOR and triggers mTORC2 activity, and that the PKC\u03b2 inhibitor Enza as well as targeting of LCP1 may provide a novel treatment approach to hypereosinophilic disorders.<\/jats:p>","DOI":"10.1002\/mc.23131","type":"journal-article","created":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T09:17:57Z","timestamp":1573031877000},"page":"87-103","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["LCP1 triggers mTORC2\/AKT activity and is pharmacologically targeted by enzastaurin in hypereosinophilia"],"prefix":"10.1002","volume":"59","author":[{"given":"Guangxin","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine RWTH Aachen University Aachen Germany"},{"name":"Hematology and Oncology Unit, Department of Geriatrics Qilu Hospital of Shandong University Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deniz","family":"Gezer","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine RWTH Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine RWTH Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Feldberg","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine RWTH Aachen University Aachen 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and Stem Cell Transplantation, Faculty of Medicine RWTH Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Koschmieder","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine RWTH Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4485-3120","authenticated-orcid":false,"given":"Nicolas","family":"Chatain","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine RWTH Aachen University Aachen 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