BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription.

The oncoprotein BCR-ABL transforms myeloid progenitor cells and is responsible for the development of chronic myeloid leukemia (CML). In transformed cells, BCR-ABL suppresses apoptosis as well as autophagy, a catabolic process in which cellular components are degraded by the lysosomal machinery. The mechanism by which BCR-ABL suppresses autophagy is not known. Here we report that in both mouse and human BCR-ABL-transformed cells, activating transcription factor 5 (ATF5), a prosurvival factor, suppresses autophagy but does not affect apoptosis. We find that BCR-ABL, through PI3K/AKT/FOXO4 signaling, transcriptionally up-regulates ATF5 expression and that ATF5, in turn, stimulates transcription of mammalian target of rapamycin (mTOR; also called mechanistic target of rapamycin), a well-established master negative-regulator of autophagy. Previous studies have shown that the BCR-ABL inhibitor imatinib mesylate induces both apoptosis and autophagy, and that the resultant autophagy modulates the efficiency by which imatinib kills BCR-ABL-transformed cells. We demonstrate that imatinib-induced autophagy is because of inhibition of the BCR-ABL/PI3K/AKT/FOXO4/ATF5/mTOR pathway that we have identified in this study.

Cost reductions associated with a quality improvement initiative for patients with ST-elevation myocardial infarction.

BACKGROUND: Efforts to reduce door-to-balloon (DTB) times for patients presenting with an ST-elevation myocardial infarction (STEMI) are widespread. Reductions in DTB times have been shown to reduce short-term mortality and decrease inpatient length of stay (LOS) in these high-risk patients. However, there is a limited literature examining the effect that these quality improvement (QI) initiatives have on patient care costs. METHODS: A STEMI QI program (Cardiac Alert Team [CAT]) initiative was instituted in July 2006 at a single tertiary care medical center located in central Massachusetts. Information was collected on cost data and selected clinical outcomes for consecutively admitted patients with a STEMI. Differences in adjusted hospital costs were compared in three cohorts of patients hospitalized with a STEMI: one before the CAT initiative began (January 2005-June 2006) and two after (October 1, 2007-September 30, 2009, and October 1, 2009-September 30, 2011). RESULTS: Before the CAT initiative, the average direct inpatient costs related to the care of these patients was $14,634, which decreased to $13,308 (-9.1%) and $13,567 (-7.3%) in the two sequential periods of the study after the CAT initiative was well established. Mean DTB times were 91 minutes before the CAT initiative and were reduced to 55 and 61 minutes in the follow-up periods (p < .001). There was a nonsignificant reduction in LOS from 4.4 days pre-CAT to 3.6 days in both of the post-CAT periods (p = .11). CONCLUSIONS: A QI program aimed at reducing DTB times for patients with a STEMI also led to a significant reduction in inpatient care costs. The greatest reduction in costs was related to cardiac catheterization, which was not expected and was likely a result of standardization of care and identification of practice inefficiencies.