Project Title: Inflammation as a Driver of Clonal Expansion in Myeloproliferative Neoplasm
Chronic inflammation is a characteristic feature of myeloproliferative neoplasm and drives many of the debilitating constitutional symptoms associated with the disease. We have previously found that JAK2V617F mutant hematopoietic progenitors are resistant to the inflammatory cytokine tumor necrosis factor-alpha. We propose that chronic inflammation plays a central role in the expansion of the neoplastic mutant clone in MPN. We have built a model whereby chronic inflammatory insult upon a vulnerable HSC pool drives the emergence of clones that have acquired mutations (i.e. JAK2V617F) that make them resistant to inflammation. Here, we will test this proposed model using MPN mice and cells from MPN patients. Our ultimate goal is to identify ways to reduce inflammation in MPN and/or protect non-mutant hematopoietic stem cells from the harmful effects of inflammation such so as to neutralize the selective advantage of the neoplastic MPN clone.