Speaker
Description
Hematopoietic stem cell (HSC) maintenance depends on the regulation of ribosome function. Mutations in ribosome-associated genes disrupt this regulation, leading to congenital disorders characterized by anemia, bone marrow failure, and an increased risk of hematologic malignancies. These pathologies are associated with the activation of the p53 stress response arising through ribosomal dysfunction. We investigated the role of MYSM1 (Myb-like, SWIRM, and MPN domains 1), a deubiquitinating enzyme and transcriptional co-activator essential for HSC maintenance and immune development. MYSM1 deficiency has been linked to p53 activation, and hematopoietic defects are rescued in Mysm1/p53 double knockout models, yet the dynamical mechanisms connecting p53 activation to bone marrow failure remain unclear. To model the regulatory interactions between MYSM1, p53, and their downstream targets in the bone marrow, we developed systems of ordinary differential equations to represent normal and aberrant hematopoietic hierarchies. Using murine experimental data, we evaluated competing mechanistic hypotheses through parameter estimation and model selection. This framework quantifies how MYSM1 deficiency perturbs hematopoietic dynamics and clarifies the contribution of p53-mediated pathways to stem cell depletion. This work provides mechanistic insight into the bone marrow failure consistent with MYSM1-related ribosomopathies, with implications for cancer predisposition and therapeutic targeting.
