ABSTRACT
A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSC). These are BCR-ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs. SIGNIFICANCE: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248-57. ©2016 AACR.See related article by Xie et al., p. 1237This article is highlighted in the In This Issue feature, p. 1197.
Subject(s)
Enhancer of Zeste Homolog 2 Protein/genetics , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/administration & dosage , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cellular Reprogramming/genetics , Drug Resistance, Neoplasm/genetics , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Epigenesis, Genetic/drug effects , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/pathology , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathologyABSTRACT
INTRODUCTION: Simulators provide a potential solution to some of the challenges faced when teaching internal examinations to medical or veterinary students. A virtual reality simulator, the Haptic Cow, has been developed to teach bovine rectal palpation to veterinary students, and significant training benefits have been demonstrated. However, the training needs to be delivered by an instructor, a requirement that limits availability. This article describes the development and evaluation of an automated version that students could use on their own. METHODS: An automated version was developed based on a recording of an expert's examination. The performance of two groups of eight students was compared. All students had undergone the traditional training in the course, namely lectures and laboratory practicals, and then group S used the simulator whereas group R had no additional training. The students were set the task of finding the uterus when examining cows. The simulator was then made available to students, and feedback about the "usability" was gathered with a questionnaire. RESULTS: The group whose training had been supplemented with a simulator session were significantly better at finding the uterus. The questionnaire feedback was positive and indicated that students found the simulator easy to use. CONCLUSIONS: The automated simulator equipped students with useful skills for examining cows. In addition, a simulator that does not need the presence of an instructor will increase the availability of training for students and be a more sustainable option for institutions.
Subject(s)
Computer Simulation , Digital Rectal Examination/methods , Rectum , Schools, Veterinary , Teaching , Veterinary Medicine/methods , Animals , Cattle , Educational Measurement , Educational Status , England , Humans , London , Models, Animal , Software , Surveys and QuestionnairesABSTRACT
Bovine rectal palpation is a necessary skill for a veterinary student to learn. However, lack of resources and welfare issues currently restrict the amount of training available to students in this procedure. Here we present a virtual reality based teaching tool -- the Bovine Rectal Palpation Simulator -- that has been developed as a supplement to existing training methods. When using the simulator, the student palpates virtual objects representing the bovine reproductive tract, receiving feedback from a PHANToM haptic device (inside a fibreglass model of a cow), while the teacher follows the student's actions on the monitor and gives instruction. We present a validation experiment that compares the performance of a group of traditionally trained students with a group whose training was supplemented with a simulator training session. The subsequent performance in the real task, when examining cows for the first time, was assessed with the results showing a significantly better performance for the simulator group.
