Team DE THÉ

Molecular Pathology

We have demonstrated that Pml controls sumoylation, coupling it to oxidative stress. Furthermore, normal Pml protein is essential for the PML/RARA fusion-induced LAP response. Work in progress shows that Pml is also important for the response to conventional chemotherapy, via the control of senescence. In both models, we are exploring the structure/function relationships of Pml (redox sensing site, sumoylation sites…).

In APL, efficient therapeutic response requires the presence of Pml, but disease initiation is linked to interference with RARA signaling. Indeed, diseases similar to classical APL have been described in patients after overexpression of RARA following viral insertion. Previous studies suggest that transcriptional repression plays a role in immortalization. We have recently demonstrated that PML-mediated sumoylation of RARA-bound proteins (notably corepressors) contributes to repress the transcription of target genes. We are also investigating the nature of the downstream targets involved in acquisition of self-renewal and differentiation blockade.

We are exploring, using single-cell transcriptomics chemotherapy responses directly in patients and identifying the gene networks mobilized in response to conventional chemotherapy. Any links with ultimate clinical responses are being unravelled.