Speaker
Description
Primary myelofibrosis (PMF) is a malignant clonal disease of the hematopoietic system. It is characterized by an excess of fiber production in the bone marrow and eventually leads to an impaired blood cell formation and an increased risk of leukemic transformation. Although driver mutations in the genes for JAK2, CALR, and MPL have been identified in most patients, the pathophysiologic mechanisms remain incompletely understood, and curative treatment options are limited.
We developed a mechanistic non-linear ordinary differential equation model to investigate the dynamic interactions between healthy and malignant hematopoietic cells during PMF progression. The model incorporates competition for niche space, fibrosis-driven niche deterioration, differentiation dynamics and feedback regulations.
The model successfully reproduces the dynamics of mature blood cells across different disease stages. In particular, leukocyte and platelet counts increase during the early disease phase and subsequently decline, consistently with clinical observations. Simulations further indicate that the clonal expansion and competition may start decades before clinical manifestation.
Our model offers mechanistic insights into how niche deterioration and stem cell competition shape disease dynamics and contribute to inter-individual heterogeneity of the clinical course. The model can be used to identify potential therapeutic strategies aimed at preserving niche function and restoring hematopoiesis.
