Impact of innate immune memory on inflammation-driven modulation of hematopoietic stem and progenitor cell populations in TET2 loss

About This Grant

PROJECT SUMMARY Myelodysplastic syndromes (MDS) are clonal, age-related bone marrow failure disorders that affect aged individuals and are met with limited treatment options, despite high rates of mortality. Mutations in ten-eleven translocation protein 2 (TET2) drive disease in MDS and associate with poor prognosis. However, some individuals with no hematopoietic disorder harbor these mutations and have low probability of progression to disease. It is unknown why some patients with TET2 loss have disease while others will not. Innate immune inflammation elicited by bacterial products drives clonal expansion and disease progression in TET2-deficient mouse models. Yet it is not understood how innate immune inflammation interacts with TET2 loss during physiological challenges throughout an individual’s lifetime, hindering development of therapies. Receptor interacting serine/threonine kinase 1 (RIPK1) plays a central role in inflammatory signaling pathways such as TLR4 signaling, and inactivation of its kinase activity alleviates some of the inflammatory repercussions of TET2 loss, revealing a potential therapeutic target. TET2 loss also impairs effective innate immune cell function and augments inflammation following bacterial infection. In WT mice, prior MPLA exposure (a toll like receptor 4 (TLR4) agonist known to initiate innate memory) improves innate immune function and dampens inflammation during subsequent bacterial infection. The objective of this proposal is to apply the powerful model of innate immune memory to TET2 deficiency and define how infection and incomplete inflammatory resolution promote disease progression. Due to the inflammatory nature of TET2 loss, I hypothesize that inflammation initiated by MPLA with infection persists, promoting disease progression. Additionally, I expect RIPK1 augments inflammation in TET2 loss, playing an essential role in disease progression. To explore these hypotheses, I will apply MPLA-induced innate immune memory to murine models of TET2 deficiency and RIPK1 inactivation, which is unique in its ability to augment pathogen clearance while simultaneously dampening inflammation. Aim 1 will utilize a slowly progressive S. aureus infection model to define innate immune cell function deficits, incomplete inflammatory resolution, and hematopoietic dysregulation in TET2 loss and the function of RIPK1 in moderating these effects. Aim 2 will then elucidate how inflammation and disease progression are altered in TET2 loss by examining differentiation and inflammatory signaling in vitro under MPLA stimulation, following which I will stimulate mice in vivo with different TLR agonists prior to infection to determine the mechanism of hematopoietic dysregulation. These Aims will collectively define how infection-induced inflammation promotes disease progression in TET2 loss, thus promoting our understanding of the biology of clonal expansion in hematologic disease in a physiologically-relevant setting. The results of these studies will have broad translational applicability to advancing treatment options for patients affected with MDS to specifically target inflammatory pathways, which minimize disease progression and improve patient outcomes.