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UBC Theses and Dissertations

The role of CD44 in the regulation of hematopoiesis Ghaffari, Saghi


The daily production of the large number of circulating blood cells is the result of a controlled process called hematopoiesis. In humans, adult hematopoiesis takes place in the bone marrow microenvironment where the regulated production and presentation of both positive and negative-acting factors control hematopoietic cell proliferation, differentiation and survival. Many cell surface molecules, including growth factor receptors and adhesion molecules are involved in these processes, although their relative importance remains to be understood. In the present thesis, I have focused on an examination of the potential role of the CD44 family of adhesion molecules in the regulation of primitive hematopoietic cell proliferation and differentiation. CD44 is a widely expressed multifunctional cell surface glycoprotein which has been implicated in many different adhesion-dependent processes. In addition, expression of particular isoforms of CD44 has been associated with malignant transformation and/or the acquisition of metastatic potential. The expression of CD44 isoforms was examined on primitive normal and myeloid leukemic hematopoietic progenitor cells. These studies have shown that the differentiation-associated changes of CD44 isoform expression is altered during leukemogenesis. In addition, monoclonal antibodies to distinct CD44 epitopes were found to have either inhibitory, enhancing, or no effect on normal, but not on CML, stromal-dependent hematopoiesis. These results provide evidence of early differentiation-associated changes in CD44 expression during normal hematopoiesis which may be deregulated in chronic phase CML as well as in a variety of other myeloid leukemias. They also identify CD44 as a putative regulatory component in the interactions of hematopoietic cells with stroma, and suggest that this function is absent in primitive CML hematopoietic cells. Future investigations of molecular mechanisms involved in the regulation of CD44 ligand-binding and its downstream effects should provide insights into the biological observations described at the cellular level in this thesis.

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