- Meeting ID: 867 6409 6440
- passcode: 149120
13h00 - 13h50 – Carine Legrand (U944, Hôpital Saint Louis)
Characterize and predict the transition to acute myeloid leukemia, using a compartmented, multitype branching model.
Patient survival to myelodysplasic syndromes (MDS) is currently unsatisfactory, essentially because of the high risk of transition to Acute Myeloid Leukemia (AML). A key feature of this transition is the evolution of hematopoietic stem cells (HSCs), which is shaped by the accumulation of somatic mutations. Remarkably, somatic mutations are also valuable observers of the molecular processes at stake, and allow to decipher these processes, using for instance estimates of Darwinian selection and of mutational signatures. However, the characterization of MDS and its transition to AML often uses a polygenic score and clinical features, but a fine-grained characterization, using modelling and the full information available from somatic mutations, is currently lacking. Such a characterization is desirable because it may inform enhanced therapeutic options, in order to slow down and finally intercept the transition to AML. Therefore, we set out to characterize and model MDS and its transition to AML using somatic mutations. Because the modelling of MDS was seldomly explored until now, we first exploit the genomic features of the evolution of HSCs, and we use simulations based on a Moran model, to nail down essential and observable parameters. We then model the evolution of HSCs using a multitype non-homogeneous branching process, with a focus on the persistence of leukemic cells, because it is an essential feature of the evolution and transition to AML. To account for the characteristics of leukemia (selection, drift), the branching process will be compartmented into subsets of stem cells. Current results at the level of genomic features indicate several convergent evolution features during the transition of MDS to AML, in a cohort of 11 patients from the THEMA study in St Louis Hospital in Paris, from the Hauts-de-France Observatory in Lille, and from Cochin Hospital in Paris. Remarkably, selection operates similarly across samples, and increases during the transition. Also, the genomic regions subjected to mutations also move from fine-tuned to more potent regulatory elements during the transition. Further supporting these convergent observations, mutational processes, quantified using mutational signatures (Alexandrov et al. Nature 2020), are homogeneous between patients, and follow the same dynamics during the transition MDS>AML. Clonal structure is currently deciphered within samples, and preliminary results of simulations indicate a good representativity of the site-frequency spectrum observed in patient data.
Dernière modification le 08/11/2024