Speaker
Description
Authors: M. Andersen, H. Hasselbalch, T. Stiehl, J.T. Ottesen
Human blood cell production is maintained by hematopoietic stem cells (HSC) which give rise to all types of mature blood cells. Experimental observation of HSC in their physiologic bone-marrow microenvironment, the so-called stem cell niche, is challenging. Therefore, the details of HSC dynamics and the cellular interactions in the stem cell niche remain elusive. Mutations that lead to a competitive advantage are the cause of clinical challenges when treating HSC-derived malignancies such as acute myeloid leukemia or the myeloproliferative neoplasms (MPN). To investigate the significance of the interaction between the HSC and the stem cell niche in these malignancies, we propose and analyse a mechanism-based mathematical model of HSC dynamics within the bone-marrow microenvironment. The JAK2V617 mutation is a key driver for overproduction of blood cells in MPN with chronic inflammation acting as an additional driver of the disease. Long-term treatment with interferon-alfa (IFN) can reduce the disease burden of MPN patients. Determining individual patient responses to IFN therapy may allow for efficient personalized treatment, reducing both drop-out and disease burden. The mathematical model is calibrated to data of the randomized trial study DALIAH. Through comprehensive modeling of the effects of IFN, the model was related to individualized patient-data consisting of longitudinal hematologic and molecular measurements. We believe that this approach could have direct clinical relevance, offering expert guidance for clinical decisions about IFN treatment of MPN patients. If time permits we will address recent findings of mathematical modeling and data of pre-disease dynamics (CHIP) as well as experimental combination therapy for MPN patients receiving IFN combined with inflammation inhibitors.
