Effect of inflammation on JAK2 mutant evolution in the hematopoietic system: mathematical models and experiments

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PROJECT SUMMARY/ABSTRACT Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V617F), which leads to excessive production of myeloid lineage cells. Patients with early stage MPN can spontaneously progress to myelofibrosis, a more aggressive stage of the disease with an average survival rate of two years. Moreover, MPN patients have a significant risk of developing acute myeloid leukemia (AML). The traditional approach to therapy in MPN is simply to reduce the risk of blood clots with aspirin, manage symptoms, and observe for progression of the disease. Therapeutic intervention is focused on patients with late stage disease, mostly due to the lack of currently available therapies that halt progression. There is thus a need for interventions that impact disease progression in MPN. Preliminary work by the laboratory of Dr. Fleischman, in collaboration with mathematical modelers Komarova and Wodarz, has shown that inflammation can accelerate the growth rate of JAK2V617F mutant cells relative to JAK2WT cells, and that this can potentially have a variety of consequences for the evolution of mutant cells at homeostasis. This suggests the possibility of a new treatment modality for early stage MPN, in which the evolutionary fate of the JAK2V617F mutants is altered and disease progression is delayed or halted. The overall goal of this proposal is to investigate how this can be achieved. In Aim 1, experiments are proposed that document the dynamics of JAK2WT and JAK2V617F mutant cells in isolation with and without inflammation for the purposes of model construction and parameterization. We will also interrogate the intracellular mechanisms responsible for the differential response of JAK2V617F mutants to inflammation. In Aim 2 we will perform experiments in which JAK2WT and JAK2V617F mutant cells are combined in mouse models with and without inflammation. This will quantify how the number of mutants influence the kinetic parameters of wild- type cells, which is important because we know that mutants themselves can increase inflammation and hence alter the dynamics. In Aim 3 we will measure how a panel of existing drugs impact the kinetic parameters of cells and use our model to predict combinations and dosing schedules that will lead to diminution of the mutant cells. Many treatment scenarios (in sequence and in combination) will be explored, and the most promising therapeutic approaches predicted by the model will be tested experimentally. This can identify better and currently unknown ways in which to utilize existing drugs. On a more exploratory level, the validated mathematical model can suggest which parameter(s) to target in which ways to make treatment more efficient than can be currently done. This information would facilitate development of future treatments and guide drug discovery and could be translated into a future clinical trial.