Cell reprogramming by oncogenic chimeric transcription factors

Summary

Many childhood sarcomas are driven by genome rearrangements that lead to the expression of oncogenic chimeric transcription factors (OCTF).

OCTF present neomoprhic properties as compared to their wild type counterparts. One example is Ewing sarcoma, a bone sarcoma, that is characterized by fusions between FET and ETS family members, most frequently EWS-FLI1. Cell-to-cell variability of EWS-FLI1 activity constitutes a major source of intra-tumor heterogeneity. Moreover, germline polymorphisms associated with susceptibility to Ewing sarcoma as well as secondary genetic alterations such as STAG2 loss-of-function are key modulators of EWS-FLI1 activity. Neomorphic ability of EWS-FLI1 to bind specific DNA sequences and to activate transcription generate exquisitely Ewing specific multi-exonic neotranscripts from otherwise silent regions of the genome that can be translated into peptides. They may thus constitute attractive targets for immunotherapies. More generally, hundreds of neotranscripts can be detected in other OCTF-driven sarcomas.

Biographie : Olivier Delattre, MD, PhD was trained in pediatric oncology and in genetics. His research area mainly investigates the genetic and biology of pediatric cancers. His laboratory has identified the genetic alterations of a variety of childhood cancers including the EWS-FLI1 rearrangement in Ewing sarcoma, the SMARCB1 inactivation in rhabdoid tumors, the ALK activation mutation in neuroblastoma and the BCOR-CCNB1 fusion in Ewing-like sarcoma. He has also contributed identifying major tumor predisposing mutations or genetic susceptibility factors in neurofibromatosis type II, rhabdoid syndrome predisposition, neuroblastoma and Ewing sarcoma. His lab has also strong interest in deciphering the cellular origin of pediatric cancers and particularly Ewing sarcoma, neuroblastoma and rhabdoid tumors and in finding new therapeutic targets in these diseases. Olivier Delattre is a member of EMBO since 2011 and of Academia Europea since 2012. He received numerous awards including the Eurocancer award in 2007, Charles Oberlin award in 2009, the Leopold Griffuel award in 2016. Olivier Delattre is Director of the Cancer, Heterogeneity, Instability and Plasticity department Inserm U830 and Director of the SIREDO center, a pediatric center that gathers researchers and physicians in the pediatric, adolescent and young adult cancer fields to bring new medications to patients as quickly as possible.

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