The course of hematopoiesis proceeds through numerous distinct maturational stages beginning with a single common ancestor of all blood cells, the hematopoietic stem cell (HSC). Upon receiving signal to differentiate, HSCs gradually restrict their differentiation potential, a process called commitment. The precise mechanisms that drive commitment to a specific lineage (e.g. lymphoid versus myeloid) are not fully understood. In our own investigations, we have found that two distinct lymphoid-committed progenitors (the common lymphoid progenitor (CLP) in the bone marrow and proT cell in the thymus) harbor a """"""""latent"""""""" granulocyte/macrophage (G/M) differentiation potential that can be triggered by ectopic IL-2 receptor signaling. In this research proposal, we focus on the biology of lymphoid progenitors in order to understand in molecular detail the process of commitment to lymphoid and myeloid lineages. First, we will examine whether G-CSF and M-CSF have instructive actions to induce granulocytes and macrophages differentiation from CLPs. Next, we will clarify the mechanisms involved in the transdifferentiation of CLPs from lymphoid to myeloid by examining regions of the IL-2 receptor beta chain that promote lineage-switching. Furthermore, we will investigate changes in gene expression in CLPs before and after ectopic IL-2 receptor signaling. Lastly, we will examine whether T, B, and NK cell-specific genes actively inhibit IL-2-induced G/M transdifferentiation of CLPs and proT cells. The results obtained from this research proposal will allow us to better understand not only normal hematopoiesis but also aberrant hemato/lymphopoiesis that can result in leukemia or immunodeficiency.
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