title: Evidence for the involvement of DNA topoisomerase II in neutrophil-granulocyte differentiation.
abstract: Agents that slow cellular proliferation usually stimulate myeloid differentiation. The demonstration in this report of an anomalous inhibitory behavior of the epipodophyllotoxin VP16-213, an agent known to inhibit the enzyme DNA topoisomerase II, prompted us to investigate the role of this enzyme in both changes in DNA supercoiling and in DNA strand breakage and reunion events occurring during the induction of neutrophil-granulocyte differentiation. We recently reported that retinoic acid, an inducer of granulocytic differentiation, stimulates transient relaxation of DNA supercoiling. We now show that this is associated with the formation of small numbers of protein-linked DNA breaks (a characteristic of topoisomerase reactions). Both events are perturbed by VP16-213, and since this agent inhibits subsequent differentiation, these observations raise the possibility of a role for DNA topoisomerase II in granulocytic differentiation. The possible relevance of these findings to mechanisms of leukemogenesis is discussed.
authors.affiliation: Department of Haematology, Royal Free Hospital School of Medicine, London, U.K.
authors.forename: G E
authors.initials: GE
authors.lastname: Francis
authors.forename: J J
authors.initials: JJ
authors.lastname: Berney
authors.forename: P S
authors.initials: PS
authors.lastname: North
authors.forename: Z
authors.initials: Z
authors.lastname: Khan
authors.forename: E L
authors.initials: EL
authors.lastname: Wilson
authors.forename: P
authors.initials: P
authors.lastname: Jacobs
authors.forename: M
authors.initials: M
authors.lastname: Ali
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology*; D006801:Humans; D009504:Neutrophils / Q000166:cytology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D014212:Tretinoin; D005047:Etoposide; D004250:DNA Topoisomerases, Type II