Mechanisms of leukemic stem cell interaction in AML: insights from complementary mathematical modeling approaches.

Abstract Acute myeloid leukemia (AML) is a severe disorder of the blood forming system which is commonly treated with cytotoxic drugs. It is still incompletely understood how the dynamic interaction between leukemia and the stem cell-niche influences AML progression, treatment outcome and resistance formation. Mathematical models provide a framework to quantitatively investigate different assumptions about these regulations, especially with respect to the regulation of stem cell proliferation, and can help to identify potential clinical targets. To this end we compare two recently published, complementary models of AML progression and treatment. Based on an analytical reformulation of the models we highlight a fundamental difference in how the models describe the regulation of proliferation. We assess the models’ suitability to describe disease dynamics and treatment outcomes by fitting each model to 275 clinical remission time courses and respective therapy cycles. Furthermore, we perform a systematic screening with univariate alterations for relevant parameters to evaluate their influence regarding velocity and depth of remission during induction therapy as well as the length of remission thereafter. The results align with the increasing consensus that therapies targeting niche-interactions mechanisms could potentially contribute to improve treatment outcomes in AML. We conclude that the regulation of normal and leukemic stem cell proliferation can be coupled to niche-dependent and niche-independent mechanisms. While both assumptions allow to sufficiently describe clinically available time course data, their complementary roles in leukemia progression but also in normal and stress hematopoiesis need to be further delineated.