Determining how inflammation is regulated in RUNX1-Familial Platelet Disorder with Associated Myeloid Malignancies

PROJECT SUMMARY RUNX1 Familial Platelet Disorder with associated myeloid malignancies (RUNX1-FPD) is caused by inherited monoallelic mutations in the RUNX1 transcription factor. RUNX1-FPD patients have a high risk of developing hematologic malignancies. Chronic inflammation is thought to play a central role in driving the risk for cancer in RUNX1-FPD. As such, controlling inflammation may be an effective therapeutic strategy for preventing cancer. However, the mechanisms by which mutations in RUNX1 promote an inflammatory state are incompletely understood. We previously showed using genetic mouse models that loss of RUNX1 epigenetically derepresses inflammatory signaling pathways in granulocyte-monocyte progenitors (GMPs). These epigenetic alterations are inherited by neutrophils, which become primed to oversecrete cytokines. The epigenetic state induced by loss of RUNX1 in GMPs strikingly resembles the proinflammatory epigenetic state of hematopoietic stem and progenitor cells (HSPCs) in trained innate immunity (TII). In TII, exposure to pathogen or damage associated molecular patterns induces HSPCs to undergo epigenetic remodeling that enables the innate immune system to respond to these stimuli more robustly in the future. In contrast to the adaptive nature of TII, complete loss of RUNX1 appears to induce a fixed and maladaptive proinflammatory state. The first goal of this proposal is to establish whether RUNX1-FPD patients exhibit a state of fixed maladaptive innate immunity. The second goal of this proposal is to determine whether and how the adaptive process of TII is altered in RUNX1-FPD. I hypothesize that fixed maladaptive innate immunity caused by decreased RUNX1 levels in hematopoietic progenitors will augment TII. I will test my hypothesis in a mouse model that faithfully recapitulates RUNX1-FPD using a high fat diet model to induce TII. These studies will provide mechanistic insight into the dynamic role that RUNX1 plays in regulating the inflammatory potential of the innate immune system and may identify opportunities to therapeutically control inflammation.