Molecular pathology

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 PBL have been described in patients after overexpression of RARA following viral insertion. Previous studies suggest that transcriptional repression plays a role in immortalization. We aim to understand the molecular mechanisms of repression and the nature of the downstream targets involved in acquiring self-renewal and blocking differentiation.

We are pursuing two approaches in parallel. One uses mouse models of AML in which the Pml gene has been inactivated. These show a blocked response to conventional chemotherapy, associated with an absence of treatment-induced senescence. The other model explores the single-cell transcriptional response directly in patients. These converging approaches address the gene networks and signaling cascades mobilized in response to conventional chemotherapy.