Computational Modeling of the Aging Human Bone Marrow and Its Role in Blood Cancer Development

ThomasStiehl

Institute for Computational Biomedicine and Disease Modeling, University Hospital RWTH Aachen, Aachen, Germany & Department of Science and Environment, Roskilde University, Roskilde, Denmark

"Computational Modeling of the Aging Human Bone Marrow and Its Role in Blood Cancer Development"

Blood cancers pose a growing medical and economic challenge in aging societies. Every day, the human bone marrow (BM) generates more than 100 billion blood cells. This process is driven by hematopoietic stem cells (HSCs), which retain their ability to proliferate and self-renew throughout life. However, over time, HSCs accumulate mutations that may lead to malignant transformation, as seen in acute myeloid leukemia (AML), one of the most aggressive cancers. Even in healthy individuals, the BM undergoes age-related changes, including a decline in cell numbers, remodeling of the BM micro-environment, and a bias in HSC differentiation. Emerging evidence suggests that these alterations create a favorable environment for the expansion of mutated cells, thereby promoting blood cancer development and progression. Mathematical and computational models facilitate our understanding of how BM aging contributes to malignant cell growth. We propose nonlinear ordinary differential equation models to describe blood cell formation and clonal competition in the human BM. The models incorporate micro-environmental and systemic feedback loops and are informed by data from both healthy individuals and cancer patients. Our findings suggest that the age-related decline in HSC self-renewal, combined with increased chronic inflammation (inflammaging), makes the BM more susceptible to the expansion of mutated cells and at the same time impairs treatment response. Through mathematical analysis, quantitative simulations, and patient data fitting, we study the following questions: 1. How do HSC proliferation & self-renewal change during physiological aging? 2. How do age-related alterations in healthy BM contribute to blood cancer development? 3. What is the impact of chronic inflammation on HSC function and blood cancer progression? 4. How do age-related BM changes affect treatment responses, e.g., in AML patients? 5. How could treatment protocols be adapted to elderly patients?
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