The Myelodysplastic Syndromes are heterogeneous, hematopoietic stem cell malignancies characterized by ineffective hematopoiesis and a high propensity for transformation to Acute Myeloid Leukemia. Despite an increasing understanding of the biological processes driving the disease, there have been limited advances in treatment options for patients over the last two decades. Further, responses to current standards are not robust and often short lived. Our research focuses on unraveling the biological processes that promote disease manifestation in an effort to develop novel therapeutic strategies that may significantly improve the disease natural history and patient outcomes. In particular, we are focused on the role of inflammation in MDS pathogenesis and how we may target critical pathways therapeutically.

Chronic inflammation is central to MDS disease pathobiology. Inflammatory inciting phenomenon result in both increased cellular self-renewal as well as increased cell death of malignant hematopoietic stem and progenitor cells (HSPC) leading to maturation blocks and inadequate differentiation, the fundamental disease characterizing defect. Concurrently, chronic inflammation suppresses normal HSPC function and provides an acquired, competitive advantage to the malignant clone fostering disease progression. We find innate immune licensing, and specifically NLRP3 inflammasome activation, contributes to chronic inflammation and occurs in the presence of vast genetic diversity in MDS patients. Our research utilizes a number of molecular and biological approaches to delineate the mechanisms of inflammasome activation and chronic inflammation in the context of this genetic diversity using developed cell line models and primary patient specimens.

To this end, Dr. McGraw serves as Principal Investigator of the MDS Natural History and Biospecimen Acquisition protocol. Utilizing a comprehensive approach, primary specimens from study participants are utilized to investigate vast cellular processes including genetic missteps, dysregulation of cellular pathways and immune regulation, altered secretion of pro-inflammatory factors, and the intricate interplay with the bone marrow microenvironment all that cause inflammation and malignant clone expansion. In addition, we will be monitoring the natural history of disease in not only adult populations but severely under-studied pediatrics and adolescences and young adults (AYA).