- Meeting ID: 867 6409 6440
- passcode: 149120
13h00 - 13h50 – Jose Sanchez Villanueva (I2M, MABioS)
Dynamical modelling of the regulatory network underlying Retinoic Acid resistance in Acute Promyelocytic Leukaemia
Acute Promyelocytic Leukaemia (APL) results from an aberrant chromosomal translocation involving the Retinoic Acid Receptor Alpha (RARA) gene, predominantly with the Promyelocytic Leukaemia (PML) or Promyelocytic Leukaemia Zinc Finger (PLZF) gene. These oncoproteins block the normal haematopoietic differentiation program and promote aberrant proliferative promyelocytes. A Retinoic Acid (RA) therapy is successful in most of the PML::RARA patients, while PLZF::RARA patients frequently display treatment resistance and relapse. We developed a logical network model integrating signalling, transcriptional and epigenetic regulatory mechanisms, which captures the key features of the APL cell responses to RA treatment depending on the genetic background. The explicit inclusion of the histone methyltransferase EZH2 allowed us to assess its role in the maintenance of the resistant phenotype, distinguishing between its canonical and non-canonical activities. The model dynamics were thoroughly analysed using a combination of tools integrated in the public software suite maintained by the CoLoMoTo consortium (https://colomoto.github.io/). All the code and results are documented in a Jupyter notebook, greatly easing the reproduction and further extensions of our analyses. Ultimately, the model serves as a solid basis to assess the roles of novel regulatory mechanisms, as well as to explore novel therapeutical approaches in silico.
Dernière modification le 05/04/2024