Project name: Homo sapiens

Description: CD99 is a transmembrane protein, whose expression is constantly associated to Ewing’s Sarcoma (EWS), a class of pediatric bone tumors with particular poor prognosis. We previously reported that engagement of CD99 leads to massive and rapid EWS cell death through a non-canonical path. Here we report that death occurs through a novel mechanism starting from classical apoptotic features, such as phosphatydilserine exposure on cell surface and mitochondrial depolarization and ending with massive cytoplasmic hypervacuolization (autophagosomes and micropinosomes). Mechanistically, CD99 induces upregulation of IGFI-R and RAS and rapid MDM2 degradation, which leads to p53 reactivation. We propose that upon CD99 engagement and subsequent p53 reactivation, the EWS-ets oncogene becomes insufficient to sustain EWS transformation; in this context, up-regulated RAS, deprived of a cooperating oncogenic stimulus, might contribute to the delivery of fatal rather than pro-survival signal. The most CD99-responsive EWS cells have either wild type or transcriptional active P53, though mutated, and greatly benefit from MDM2 degradation. Due to the low rate of P53 inactivating mutations in EWS patients, these findings sustain CD99-targeting with specific MAbs either to directly kill EWS cells or to increase sensitivity to chemotherapy. By recruiting also RAS, CD99 delivers a signal which exceeds that of drugs designed exclusive to reactivate p53 functions, besides being easily druggableOverall design: Ewing Sarcoma cell lines 6647 control or treated with the anti-CD99 0662 MAb were profiled to discover mechanisms related to CD99 targeting. Treated cells were compared to control cells after 30, 60 and 120 minutes of exposure to 0662 (10µg/ml); all treatments are in duplicate.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: Medical

Last updated: 2012-02-27