MicroRNAs in Normal and Malignant Myelopoiesis

__abstract__ Hematopoiesis is the lifelong continuous process in which hematopoietic stem and progenitor cells (HSPCs) proliferate and differentiate towards mature blood cells. Hematopoiesis is tightly controlled by a network of growth factors and the hematopoietic niche in the bone marrow (BM). This ensures the balanced blood cell production under homeostatic conditions and allows for transient elevation of specific blood cell types production in response to infections or bleeding 1. In mammalian organisms, long-term hematopoietic stem cells (LT-HSCs) reside in the BM and have self-renewal capacity over the lifespan of the organism 2,3. The estimated amount of LT-HSCs is approximately 0.007% of all hematopoietic cells in the BM 4. LT-HSCs give rise to short-term HSCs (ST-HSCs) and multipotent progenitors (MPPs) (Figure 1). These cells have the potential to differentiate into all the different hematopoietic cell types but have less self-renewal capacity 4. Together, LT-HCSs, ST-HCSs and MPPs constitute 0.05% of mouse BM cells 2. MPPs differentiate into common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs) (Figure 1). Subsequently, CLPs differentiate into B-cell and T-cell lineages. CMPs first develop into more specified myeloid progenitors, which are megakaryocyte/erythroid progenitors (MEPs) and granulocyte/monocyte progenitors (GMPs). Granulocytes, monocytes and macrophages arise from GMPs, whereas MEPs differentiate towards erythrocytes and thrombocytes (platelets) (Figure 1). The process of differentiation of HSPCs towards mature myeloid cells is referred as myelopoiesis. In adult mammalian organisms, myelopoiesis occurs in the BM. Disruption of the balance between cell proliferation, differentiation and cell death leads to different hematopoietic disorders, e.g., leukemia, characterized by proliferation of undifferentiated cells, or bone marrow failure (BMF), characterized by impaired hematopoiesis involving one or multiple hematopoietic lineages 5,6. Proliferation and differentiation of HSPCs are coordinated by gene expression programs driven by endogenous and exogenous factors. MicroRNAs (miRNAs) are a class of non-coding RNAs which function as regulators of gene expression. In the studies described in this thesis the role of miRNAs in normal myelopoiesis and their involvement in acute myeloid leukemia (AML) and Fanconi anemia (FA), the most frequent inherited form of BMF syndromes are investigated. AML, FA and miRNAs will be further introduced in the following sections