The aim is to study the molecular basis of differentiation of normal and luekemic human myeloid hematopoietic cells through an analysis of genes which are specifically activated or repressed during the course of myeioid differentiation. In the bone marrow, normal immature myeloid precursor cells (myeloblasts) undergo a process of differentiation resulting in the loss of proliferative and selfrenewal capacity and the production of mature myeloid cells (i.e., granulocytes and macrophages), which are essential for fighting infection. In acute myelogenous leukemi (AML) this differentiation process is blocked, resulting in an accumulation of immature blast cells and a paucity of mature cells in the blood. Through the use of recombinant DNA technmiques, an attempt shall be made to clone genes that are either activated or repressed during the course of myeloid differentiation. By studying the structure of these genes and their expression during the course of myeloid differentiation in normal and leukemic cells, it may be possible to udnerstand the molecular mechanism of their regulation and to identify the genes responsible for inducing normal differentiation. Furthermore, by comparison of normal versus leukemic gene expression, it may be possible to identify genes which are responsible for the failure of differentiation observed in AML. Eventually an attempt shall be made to use DNA mediated gene transfer to introduce cloned genes into myeloid cells in order to study their regulation and to understand their role in inducing differentiation, as well as to understand the block in differentiation present in acute myelogenous leukemia.
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