title: PLC-beta2 monitors the drug-induced release of differentiation blockade in tumoral myeloid precursors.
abstract: The differentiation therapy in treatment of acute promyelocytic leukemia (APL), based on the administration of all-trans retinoic acid (ATRA), is currently flanked with the use of As2O3, a safe and effective agent for patients showing a resistance to ATRA treatment. A synergy between ATRA and As3O3 was also reported in inducing granulocytic differentiation of APL-derived cells. We have demonstrated that phospholipase C-beta2 (PLC-beta2), highly expressed in neutrophils and nearly absent in tumoral promyelocytes, largely increases during ATRA treatment of APL-derived cells and strongly correlates with the responsiveness of APL patients to ATRA-based differentiating therapies. Here we report that, in APL-derived cells, low doses of As3O3 induce a slight increase of PLC-beta2 together with a moderate maturation, and cooperate with ATRA to provoke a significant increase of PLC-beta2 expression. Remarkably, the amounts of PLC-beta2 draw a parallel with the differentiation levels reached by both ATRA-responsive and -resistant cells treated with ATRA/As2O3 combinations. PLC-beta2 is not necessary for the progression of tumoral promyelocytes along the granulocytic lineage and is unable to overcome the differentiation block or to potentiate the agonist-induced maturation. On the other hand, since its expression closely correlates with the differentiation level reached by APL-derived cells induced to maturate by drugs presently employed in APL therapies, PLC-beta2 represents indeed a specific marker to test the ability of differentiation agents to induce the release of the maturation blockade of tumoral myeloid precursors.
authors.affiliation: Signal Transduction Unit/Laboratory of Cell Biology, Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Brugnoli
authors.forename: Matteo
authors.initials: M
authors.lastname: Bovolenta
authors.forename: Mascia
authors.initials: M
authors.lastname: Benedusi
authors.forename: Sebastianó
authors.initials: S
authors.lastname: Miscia
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.forename: Valeria
authors.initials: V
authors.lastname: Bertagnolo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D054799:Phospholipase C beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014212:Tretinoin / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D006131:Growth Inhibitors; D010087:Oxides; D014212:Tretinoin; C518036:PLCB2 protein, human; D054799:Phospholipase C beta; D000077237:Arsenic Trioxide