title: Panobinostat (LBH589)-induced acetylation of tubulin impairs megakaryocyte maturation and platelet formation.
abstract: Drug-induced thrombocytopenia often results from dysregulation of normal megakaryocytopoiesis. In this study, we investigated the mechanisms responsible for thrombocytopenia associated with the use of Panobinostat (LBH589), a histone deacetylase inhibitor with promising anti-cancer activities. The effects of LBH589 were tested on the cellular and molecular aspects of megakaryocytopoiesis by utilizing an ex vivo system in which mature megakaryocytes (MK) and platelets were generated from human primary CD34(+) cells. We demonstrated that LBH589 did not affect MK proliferation or lineage commitment but inhibited MK maturation and platelet formation. Although LBH589 treatment of primary MK resulted in hyperacetylation of histones, it did not interfere with the expression of genes that play important roles during megakaryocytopoiesis. Instead, we found that LBH589 induced post-translational modifications of tubulin, a nonhistone protein that is the major component of the microtubule cytoskeleton. We then demonstrated that LBH589 treatment induced hyperacetylation of tubulin and alteration of microtubule dynamics and organization required for proper MK maturation and platelet formation. This study provides new insights into the mechanisms underlying LBH589-induced thrombocytopenia and provides a rationale for using tubulin as a target for selective histone deacetylase inhibitor therapies to treat thrombocytosis in patients with myeloproliferative neoplasms.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine and The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029, USA. camelia.iancu-rubin@mssm.edu
authors.forename: Camelia
authors.initials: C
authors.lastname: Iancu-Rubin
authors.forename: David
authors.initials: D
authors.lastname: Gajzer
authors.forename: Goar
authors.initials: G
authors.lastname: Mosoyan
authors.forename: Faye
authors.initials: F
authors.lastname: Feller
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019337:Hematologic Neoplasms / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology*; D007211:Indoles; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077767:Panobinostat; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000502:physiology; D013921:Thrombocytopenia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D034061:Thrombopoiesis / Q000187:drug effects* / Q000502:physiology; D014404:Tubulin / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D014404:Tubulin; D000077767:Panobinostat