title: Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis.
abstract: Imetelstat (GRN163L) is a specific telomerase inhibitor that has demonstrated clinical activity in patients with myeloproliferative neoplasms (MPN) and in patients with solid tumors. The antitumor effects were associated with the development of thrombocytopenia, one of the common side effects observed in patients treated with imetelstat. The events underlying these adverse effects are not apparent. In this report, we investigated the potential mechanisms that account for imetelstat's beneficial effects in MPN patients and the manner by which imetelstat treatment leads to a reduction in platelet numbers. Using a well-established system of ex vivo megakaryopoiesis, we demonstrated that imetelestat treatment affects normal megakaryocyte (MK) development by exclusively delaying maturation of MK precursor cells. By contrast, additional stages along MPN MK development were affected by imetelstat resulting in reduced numbers of assayable colony-forming unit MK and impaired MK maturation. In addition, treatment with imetelstat inhibited the secretion of fibrogenic growth factors by malignant but not by normal MK. Our results indicate that the delay observed in normal MK maturation may account for imetelstat-induced thrombocytopenia, while the more global effects of imetelstat on several stages along the hierarchy of MPN megakaryopoiesis may be responsible for the favorable clinical outcomes reported in MPN patients.
authors.affiliation: The Tisch Cancer Institute, Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: G
authors.initials: G
authors.lastname: Mosoyan
authors.affiliation: Center for Therapeutic Antibody Development, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kraus
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: F
authors.initials: F
authors.lastname: Ye
authors.affiliation: OncoMed Pharmaceuticals, Redwood City, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Eng
authors.affiliation: Department of Medicine-Hematology/Oncology, Northwestern University Feinberg School of Medicine, Evanston, IL, USA.|Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Evanston, IL, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Crispino
authors.affiliation: The Tisch Cancer Institute, Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: R
authors.initials: R
authors.lastname: Hoffman
authors.affiliation: The Tisch Cancer Institute, Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY USA.
authors.forename: C
authors.initials: C
authors.lastname: Iancu-Rubin
mesh_terms: D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009841:Oligonucleotides; D011123:Polyploidy; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D019098:Telomerase; C519562:imetelstat