title: Disruption of pre-B-cell receptor signaling jams the WNT/β-catenin pathway and induces cell death in B-cell acute lymphoblastic leukemia cell lines.
abstract: Targeting components of the B-cell receptor (BCR) pathway have dramatically improved clinical outcomes in a variety of B-cell malignancies. Despite the well-documented pathogenic role of BCR precursor (pre-BCR) pathway in B-cell acute lymphoblastic leukemia (B-ALL), there is limited available data of therapies that aim to disrupt this pathway. To investigate the role of protein kinase Cβ (PKCβ), a crucial mediator of BCR and pre-BCR signaling, in B-ALL survival, we studied the activity of the PKCβ selective inhibitor enzastaurin (ENZ) in seven B-ALL cell lines. Treatment with ENZ resulted in a dose- and time-dependent growth inhibition in all cell lines with a relatively higher efficacy in pro-B ALL with translocation t(4;11)(q21;q23). The mechanism of growth inhibition was by apoptotic induction and cell cycle arrest. A rapid reduction in phosphorylation of AKT and its downstream target glycogen synthase kinase 3β (GSK3β) were observed at 30min after treatment and remaining for 48h. The reduction in GSK3β phosphorylation was associated with a paradoxical accumulation of β-catenin, which was due to a transient loss of β-catenin phosphorylation at ser33-37. In addition, accumulation of β-catenin was associated with downregulation of c-Myc, upregulatiuon of c-Jun, and a subsequent protective effect on the tumor suppressor p73. Data in this paper were presented in part at 2012 American Society of Hematology Annual Meeting, abstract 1350.
authors: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, LA 70112, USA. Electronic address: nsaba@tulane.edu.
authors: Nakhle S
authors: NS
authors: Saba
authors: Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors: Magdalena
authors: M
authors: Angelova
authors: Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, LA 70112, USA.
authors: Patricia A
authors: PA
authors: Lobelle-Rich
authors: Department of Microbiology and Immunology, Tulane University, New Orleans, LA 70112, USA.
authors: Laura S
authors: LS
authors: Levy
keywords: Acute lymphoblastic leukemia; Catenin; Enzastaurin; JUN; MYC; Protein kinase Cβ