Hematopoiesis is a developmental process during which a few hematopoietic stem cells (HSC) develop and differentiate into multiple lineages of blood cells. Interestingly, recent experiments show that blood tumors such as leukemia also have a similar developmental hierarchy, in which a few leukemia stem cells (LSC) function as self-renewable "seeds" that continuously populate the entire tumors. Since both HSC and LSC are slowly proliferating cells and are more difficult to eliminate by routine chemotherapy, it is fundamentally important to understand how these stem cell functions (including differentiation and self-renewal) are controlled intracellularly by various mechanisms. MicroRNA (miRNA) of ~22-nucleotides is a class of newly discovered regulators of gene expression and plays an important role in a variety of biological processes. However, the physiological and pathological roles of these molecules in stem cell biology and leukemogenesis remain to be explored. The goal of this proposal is to investigate the role of miRNAs, miR-29a, in hematopoiesis and leukemogenesis. This subject is based on our recent findings showing that: 1) miR-29a is highly expressed in hematopoietic stem cells (HSC) and downregulated in hematopoietic lineage progenitors. 2) miR-29a overexpression in HSCs blocks B-cell development. It also leads to myeloid proliferative disorders and eventually development of acute myeloid leukemia (AML). 3) miR-29a is upregulated in about 50% of human AML. In this proposal, we will test the hypothesize that miR-29a regulates the expression of genes that control HSC and LSC function and dysregulation of miR-29a expression may lead to myeloproliferative disorder and AML, using various animal models co-developed by Dr. Fei's and Dr. Gu's laboratories. Completion of this work will help to elucidate the role and mechanisms by which miR-29a regulates hematopoiesis and leukemia genesis. It may also provide a useful target to treat leukemia such as AML.