miR-9/9* in Myeloid Development and Acute Myeloid Leukemia

miR-9/9 have been shown to be deregulated in different types of human cancer including lymphoid and myeloid malignancies. Nevertheless, we still lack the more comprehensive knowledge about the impact of miR-9/9 expression on normal hematopoietic cell function and their possible impact in the biology of AML.
In Chapter 2, we aim to elucidate the function of miR-9/9 in normal myeloid differentiation. We use murine myeloid 32D cell line model and murine primary HSPCs to investigate the impact of miR-9/9 overexpression on granulocytic differentiation induced by G-CSF. We also examine the effect of miR-9/9 expression in human primary AML samples. Further, we set out to identify miR-9/9 targets that are common for murine and human cells and that may be relevant for the observed phenotype. In Chapter 3, we broaden our quest for direct and indirect targets that are regulated by miR-9/9 by analyzing proteome changes in 32D cells. We examine the deregulated proteins and the involved pathways that could potentially influence different aspects of normal hematopoietic cell function. Our observations are further extended by in vivo and in vitro experiments presented in Chapter 4, we investigate the influence of miR-9/9 expression on homing of normal HSPCs in the BM.
Until now, few miRNAs have been shown to exhibit a prognostic value in AML. In Chapter 5, based on our results about the expression of miR-9/9 in AML patients (shown in Chapter 1), we set out to investigate whether the expression of miR-9/9 may predict patient outcome in AML.
Finally, the results presented in this thesis are summarized and discussed in Chapter 6. Here we put the accumulated insights about the functions of miR-9/9* into the broader perspective of human cancer.