ABSTRACT
Fanconi D2 (FANCD2) is monoubiquitinated on K561 (FANCD2-Ub) in response to DNA double-strand breaks (DSBs) to stimulate repair of these potentially lethal DNA lesions. FANCD2-Ub was upregulated in CD34+ chronic myeloid leukemia (CML) cells and in BCR-ABL1 kinase-positive cell lines in response to elevated levels of reactive oxygen species (ROS) and DNA cross-linking agent mitomycin C. Downregulation of FANCD2 and inhibition of FANCD2-Ub reduced the clonogenic potential of CD34+ CML cells and delayed BCR-ABL1 leukemogenesis in mice. Retarded proliferation of BCR-ABL1 positive FANCD2-/- leukemia cells could be rescued by FANCD2 expression. BCR-ABL1 positive FANCD2-/- cells accumulated more ROS-induced DSBs in comparison with BCR-ABL1 positive FANCD2+/+ cells. Antioxidants diminished the number of DSBs and enhanced proliferation of BCR-ABL1 positive FANCD2-/- cells. Expression of wild-type FANCD2 and FANCD2(S222A) phosphorylation-defective mutant (deficient in stimulation of intra-S phase checkpoint, but proficient in DSB repair), but not FANCD2(K561R) monoubiquitination-defective mutant (proficient in stimulation of intra-S phase checkpoint, but deficient in DSB repair) reduced the number of DSBs and facilitated proliferation of BCR-ABL1 positive FANCD2-/- cells. We hypothesize that FANCD2-Ub has an important role in BCR-ABL1 leukemogenesis because of its ability to facilitate the repair of numerous ROS-induced DSBs.
Subject(s)
Fanconi Anemia Complementation Group D2 Protein/physiology , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/etiology , Ubiquitination , Animals , Cell Line , DNA Breaks, Double-Stranded , Humans , Mice , Mice, Inbred C57BL , Mice, SCID , Mitomycin/pharmacology , Reactive Oxygen Species/metabolismABSTRACT
Cholestatic jaundice developed in four patients after the administration of prajmalium bitartrate. The clinical, histologic, ultrastructural, and immunologic findings were determined. In all patients, the clinical and morphologic features indicated idiosyncrasy. Two antibodies distributed in a granular pattern along the bile canaliculi were detected by immunofluorescence in all patients. In one patient, autoimmune markers were found in the serum, and in two instances, the migration-inhibition factor assay against the offending drug was found to be positive. The data support the concept that immunologic processes may participate in the production of the cholestatic syndrome.
Subject(s)
Ajmaline/analogs & derivatives , Cholestasis/chemically induced , Prajmaline/adverse effects , Aged , Antibodies/analysis , Antigen-Antibody Reactions , Cholestasis/immunology , Cholestasis/pathology , Complement System Proteins/analysis , Female , Humans , Immunoglobulins/analysis , Liver/immunology , Liver/pathology , Lymphocytes/immunology , Male , Middle Aged , Prajmaline/immunologyABSTRACT
Nine patients are reported who developed hepatic injury following the administration of therapeutic agents. The drugs incriminated were prajmalium bitartrate (4 patients), quinidine (3 patients), procainamide and nifedipine (one patient each). In all patients the clinical features indicated an allergic process, which in three cases was substantiated by positive response to reexposure. The detection of immunologic processes in our patients by various in vitro methods supports the assumption that immune mechanisms may be involved in the production of drug-induced hepatic disease and confirm allergy.
Subject(s)
Chemical and Drug Induced Liver Injury/immunology , Drug Hypersensitivity/immunology , Aged , Chemical and Drug Induced Liver Injury/pathology , Female , Fluorescent Antibody Technique , Granuloma/pathology , Humans , Immunoglobulin A/analysis , Immunoglobulin G/analysis , Liver/pathology , Male , Microscopy, Electron , Middle Aged , Nifedipine/immunology , Prajmaline/immunology , Procainamide/immunology , Quinidine/immunologyABSTRACT
Cholestatic jaundice associated with chills, pruritus and blood eosinophilia developed in a patient who received prajmalium bitartrate therapy for ventricular arrhythmia following acute myocardial infarction. Discontinuation of the drug resulted in a spontaneous improvement in the clinical and biochemical findings. Challenge by prajmalium bitartrate caused rapid reappearance of the clinical and biochemical features. In immunological studies, deposits of IgG and IgA were detected at the bile canaliculi by fluorescent staining, and the patient's lymphocytes produced macrophage migration inhibition after in vitro incubation with prajmalium bitartrate. Thus, laboratory results support the assumption of an allergic mechanism.
