Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma.

The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient-sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC-driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR-15a. TSC1 knockdown results in elevated mTORC1-dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC-driven cancers.

Deregulation of E2-EPF ubiquitin carrier protein in papillary renal cell carcinoma.

Molecular pathways associated with pathogenesis of sporadic papillary renal cell carcinoma (PRCC), the second most common form of kidney cancer, are poorly understood. We analyzed primary tumor specimens from 35 PRCC patients treated by nephrectomy via gene expression analysis and tissue microarrays constructed from an additional 57 paraffin-embedded PRCC samples via immunohistochemistry. Gene products were validated and further studied by Western blot analyses using primary PRCC tumor samples and established renal cell carcinoma cell lines, and potential associations with pathologic variables and survival in 27 patients with follow-up information were determined. We show that the expression of E2-EPF ubiquitin carrier protein, which targets the principal negative regulator of hypoxia-inducible factor (HIF), von Hippel-Lindau protein, for proteasome-dependent degradation, is markedly elevated in the majority of PRCC tumors exhibiting increased HIF1α expression, and is associated with poor prognosis. In addition, we identified multiple hypoxia-responsive elements within the E2-EPF promoter, and for the first time we demonstrated that E2-EPF is a hypoxia-inducible gene directly regulated via HIF1. These findings reveal deregulation of the oxygen-sensing pathway impinging on the positive feedback mechanism of HIF1-mediated regulation of E2-EPF in PRCC.

Choroid plexus tumors differ from metastatic carcinomas by expression of the excitatory amino acid transporter-1.

Tumors of the choroid plexus (CPTs) are rare neoplasms of neuroectodermal origin usually arising in pediatric patients. However, CPT may occur at any age, and their distinction from metastatic carcinomas is often difficult in adult cases. Because CPTs frequently show focal glial differentiation, we now investigated 35 CPTs (19 males and 16 females 0.3-70 years old; median age, 25.0 years), including 21 choroid plexus papillomas (CPPs), 5 atypical CPP, and 9 choroid plexus carcinomas regarding their expression of the excitatory amino acid transporter-1 (EAAT1, corresponding to rodent GLAST/GLAST-1) by immunohistochemistry. In addition, 77 metastatic carcinomas, including 64 adenocarcinomas with mostly papillary formations, derived from different organs were examined. Of the 35 CPTs, 23 (66%) showed membranous EAAT1 expression in variable numbers of tumor cells, including all atypical CPP and 3 of 9 choroid plexus carcinomas (33%). None of the metastatic carcinomas showed membranous immunostaining. Excitatory amino acid transporter-1 expression in CPT was significantly age dependent (P < .0001), with the proportion of EAAT1-positive tumor cells increasing with age, but not sex dependent. There was a highly significant difference between EAAT1 expression in CPT and in metastatic carcinomas (P < .0001). Establishing a cutoff value of 1% immunoreactive tumor cells served in adult cases to distinguish CPT from metastatic adenocarcinomas with 100% specificity and 70% sensitivity and was associated with positive and negative predictive values of 100% and 91%, respectively. Our findings indicate that EAAT1 immunohistochemistry may be useful in differentiating CPT from metastatic carcinomas.

Spontaneous thoracic air-leakage syndrome in patients following allogeneic hematopoietic stem cell transplantation: causes, CT-follow up and patient outcome.

OBJECTIVE: The purpose of this article is to describe and illustrate the acute and follow-up imaging features, clinical constellation and outcome of patients with thoracic air-leakage syndrome following allogeneic hematopoietic stem cell transplantation (allo-HCT). METHODS: Patients with evidence of thoracic air-leakage, i.e. spontaneous pneumomediastinum, spontaneous pneumothorax or interstitial emphysema after allo-HCT were retrospectively identified by a chart review. Acute and follow-up morphology, duration and patient outcome were analyzed on CT (HRCT or MSCT with HR-reconstructions). Correlation was made with histological results of transbronchial biopsy. RESULTS: The 6 patients included (3 male and 3 female, 14-64 years old) with thoracic air-leakage after allo-HCT all had histologically proven bronchiolitis obliterans (BO) or bronchiolitis obliterans organizing pneumonia (BOOP). Thoracic air-leakage consisted of spontaneous pneumomediastinum associated with active invasive pulmonary aspergillosis (IPA) in 4/6 and spontaneous pneumothorax or interstitial emphysema each in 1/6 patients. Duration of thoracic air-leakage was 7-135 days. Of the patients with spontaneous pneumomediastinum, 3/4 died of IPA. One patient survived until complete regression of spontaneous pneumomediastinum. One patient died 7 days after spontaneous pneumothorax and one survived developing chronic interstitial emphysema. CONCLUSION: In all cases, thoracic air-leakage was associated to BO or BOOP. In the majority of cases with additional IPA, thoracic air-leakage is more indicative for severity of pulmonary disease than a life-threatening entity itself.