TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L.

BACKGROUND: Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through the derepression of targets downstream of the mitogen-activated protein kinase (MAPK) signaling cascade, such as oncogenic E26 transformation-specific (ETS) transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in both developmental and disease contexts to facilitate the repression of CIC target genes and promote the post-translational stability of CIC. However, little is known about the mechanisms at the base of ATXN1L-mediated CIC post-translational stability. RESULTS: Functional in vitro studies utilizing ATXN1LKO human cell lines revealed that loss of ATXN1L leads to the accumulation of polyubiquitinated CIC protein, promoting its degradation through the proteasome. Although transcriptomic signatures of ATXN1LKO cell lines indicated upregulation of the mitogen-activated protein kinase pathway, ERK activity was found to contribute to CIC function but not stability. Degradation of CIC protein following loss of ATXN1L was instead observed to be mediated by the E3 ubiquitin ligase TRIM25 which was further validated using glioma-derived cell lines and the TCGA breast carcinoma and liver hepatocellular carcinoma cohorts. CONCLUSIONS: The post-translational regulation of CIC through ATXN1L and TRIM25 independent of ERK activity suggests that the regulation of CIC stability and function is more intricate than previously appreciated and involves several independent pathways. As CIC status has become a prognostic factor in several cancer types, further knowledge into the mechanisms which govern CIC stability and function may prove useful for future therapeutic approaches.

Levofloxacin for febrile neutropenia prophylaxis in acute myeloid leukemia patients associated with reduction in hospital admissions.

PURPOSE: The purpose of this study is to evaluate the efficacy and safety of prophylactic oral levofloxacin in acute myeloid leukemia (AML) patients after receiving consolidation chemotherapy to prevent febrile neutropenia. METHODS: We conducted a retrospective chart review of 50 AML patients who were prescribed levofloxacin and 50 AML patients who were not prescribed levofloxacin post-consolidation chemotherapy between June 2006 and August 2013 at a tertiary academic medical center. The primary outcome of this study was to evaluate the effectiveness of levofloxacin in preventing hospital readmission due to febrile neutropenia. Secondary outcomes evaluated the safety of this therapy, including the rate of Clostridium difficile-associated diarrhea (CDAD) within 30 days from discharge of receiving consolidation chemotherapy and rate of fluoroquinolone resistance in positive bacterial cultures. RESULTS: Hospital readmission due to febrile neutropenia after the first consolidation cycle occurred in 42% of patients prescribed levofloxacin, as compared to 72% that were not prescribed levofloxacin (p = 0.002). This was also significantly reduced when levofloxacin was prescribed after all consolidation cycles (51.4 vs. 67%, p = 0.023). CDAD did not occur in any patient prescribed levofloxacin after the first cycle, compared to one case in those not prescribed levofloxacin. Evaluation of the impact on fluoroquinolone resistance was limited due to a paucity of fluoroquinolone susceptibilities reported. CONCLUSIONS: Prescribing oral levofloxacin post-consolidation chemotherapy in AML patients is associated with a reduction in febrile neutropenia. Further research is required to identify the impact on fluoroquinolone resistance and risk of CDAD.