The Role of MiRNA Clusters Mirn23a and Mirn23b in Hematopoietic Development and Macrophage Function

Hematopoietic stem and progenitor cells (HSPCs) make up the foundation of the blood hierarchy. HSPCs differentiate down specific lineage trees towards mature blood cells responsible for systemic oxygen transport (erythrocytes) and immune cells responsible for host defense. This differentiation process is coordinated by a host of factors including transcription factors and cytokines. Recently the role of microRNAs (miRNAs) in this process has garnered more appreciation. MiRNAs are small, non- coding RNAs that have direct regulatory capacity over both the lineage commitment process as well as immune cell functions upon terminal differentiation. The aim of this dissertation was to illuminate the role of miRNA cluster mirn23a in macrophage function as well as in acute myeloid leukemia (AML). In chapter 2, I isolate primary bone marrow derived macrophages (BMDMs) from mirn23a germline knockout mice and observe that loss of mirn23a results in a more anti-inflammatory macrophage. I then investigate the physiological impact of losing mirn23a expression in the tumor microenvironment. Chapter 3 focuses on the physiological consequences of mirn23a and mirn23b loss (mirn23a-/- and mirn23a-/-mirn23b-/-) in hematopoietic stem cell (HSC) health and disease. This chapter shows that mirn23a and mirn23b expression is important to HSC fitness has a strikingly opposite influence under leukemic context by investigating if mirn23a acts as a tumor suppressor or oncogene in AML driven by the fusion protein AML1- ETO. Together, this work augments our understanding of how miRNA dysregulation leads to disease and how to better treat these conditions.