Lineage commitment to a T

Sammanfattning: he hematopoietic development is a highly dynamic but tightly regulated process. The flexibility to produce blood cells through more than one route will allow the blood system to respond rapidly in stress situations such as infections. On the other hand, regulation of the blood system is required to prevent blood cells from uncontrolled proliferation that could result in leukemia or bone marrow failure due to depletion of blood cells. Hematopoietic stem cells are cells that can differentiate to all blood lineages and maintain the whole hematopoietic system throughout a lifetime. This differentiation process through which stem cells generate mature blood cells occurs through different lineage commitment steps. The precise mapping of the lineage commitment events in normal hematopoietic development is essential to understand its regulation and also to unravel the underlying mechanisms in various hematological diseases. The aim of my thesis has been to study and delineate early lineage commitment processes in the hematopoietic stem cell compartment and in lymphopoiesis with a particular emphasis on T cell development in adult and fetal hematopoiesis using the mouse as a model system. In the thesis I present studies that support an alternative lineage commitment model to the classical and prevailing one for hematopoietic development. In the alternative model hematopoietic stem cells generate progenitors with lymphoid/myeloid (granulocyte/monocyte) and megakaryocyte/erythrocyte/myeloid fates as a first step in their lineage commitment. As the progenitors go through the differentiation to become T cells, they do not commit to a final T cell fate until they have reached and entered their final destination, the thymus. In my studies we demonstrate that the progenitor that initially seeds the thymus during early embryonic development and replenishes the thymus postnatally is more multipotent than previously appreciated. This model has not only identified new and critical commitment steps but also provides a better candidate target cell for the origin of biphenotypic leukemia, which is characterized by lymphoid and myeloid phenotypes.