ABSTRACT
The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and progression; however, the precise mechanism by which CALM-AF10 alters HOXA gene expression is unclear. We previously determined that CALM contains a CRM1-dependent nuclear export signal (NES), which is both necessary and sufficient for CALM-AF10-mediated leukemogenesis. Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression. We show that CRM1 localizes to HOXA loci where it recruits CALM-AF10, leading to transcriptional and epigenetic activation of HOXA genes. Genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin, resulting in immediate loss of transcription. These results provide a comprehensive mechanism by which the CALM-AF10 translocation activates the critical HOXA cluster genes. Furthermore, this report identifies a novel function of CRM1: the ability to bind chromatin and recruit the NES-containing CALM-AF10 transcription factor.
Subject(s)
Gene Expression Regulation, Leukemic , Homeodomain Proteins/metabolism , Karyopherins/physiology , Oncogene Proteins, Fusion/physiology , Receptors, Cytoplasmic and Nuclear/physiology , Animals , Cell Line, Tumor , Cell Transformation, Neoplastic , Chromatin Immunoprecipitation , Fatty Acids, Unsaturated/chemistry , Fibroblasts/metabolism , Gene Expression Profiling , HEK293 Cells , Humans , Luciferases/metabolism , Mice , Multigene Family , Oncogene Proteins, Fusion/genetics , Transcription, Genetic , U937 Cells , Exportin 1 ProteinABSTRACT
This descriptive study explored the type, frequency, and duration of contacts experienced by 11 mechanically-ventilated infants, born between 23 and 29 weeks gestation. A no-concealment, no-intervention, continuous observation method was utilized. Parameters recorded were: type of contact, type of caregiver, and contact duration. A total of 645 contacts were made over 1210 minutes of observation; 64.5% were indirect and 35.5% were direct. Treatment-oriented procedures accounted for 27.4% of contacts, while 63.7% were incidental. Nurses provided 82.6% of all contacts. The frequency of indirect contacts was negatively related to gestational age. The total duration of direct contacts over 1100 minutes of observation was 186.8 minutes. Nurses are challenged to coordinate necessary care with comfort measures and to decrease the frequency of disruptive contacts with premature infants.
Subject(s)
Caregivers/psychology , Infant, Premature/psychology , Nurse-Patient Relations , Respiration, Artificial/psychology , Touch , Apgar Score , Blood Gas Analysis , Female , Gestational Age , Humans , Infant, Newborn , Intensive Care Units, Neonatal , Male , Nursing Evaluation Research , Parent-Child Relations , Physical Stimulation , Physician-Patient Relations , Respiration, Artificial/nursingABSTRACT
Observations of sick infants' feeding patterns suggest that changes occur which are specific to certain illness conditions. These changes may disrupt the feeding synchrony that had been established early in the infant's development. Little research has been done on differences in feeding behaviors of infants when they become sick with a specific illness condition. This research study investigated the differences in specific feeding behaviors of infants when they were sick with an acute respiratory condition compared to when they were well. In this comparative descriptive study, infants 1 to 4 months of age were observed in their homes. The study sample consisted of 16 full-term infants who were bottlefed and became ill with a respiratory infection. Infants were videotaped during two feedings when they were ill and one feeding when they were well. Caregiver questionnaires and videotapes were the data collection tools. The videotapes were analyzed using an Infant Feeding Behavior Assessment Checklist which measures four categories of feeding behaviors: type of seal around nipple, suck-pause pattern, suck-swallow pattern, and respiratory pattern. Descriptive statistics assisted in the exploration of differences that existed between the infants' sick and well feeding behaviors. Analysis indicated that there were differences in the infants' sick and well feeding behaviors. When well, infants appeared to smoothly coordinate their suck-swallow and breathe cycle. When sick, the infants had an erratic suck-pause pattern, loosened their seal around the nipple, and had an irregular respiratory pattern with some degree of respiratory distress.
