Blood cells are built from hematopoietic stem cells in bone marrow throughout life. The hematopoietic cells have the fascinating ability to proliferate and differentiate into distinct lineages of mature blood cells including lymphocytes, erythrocytes and monocytes. Commitment of the hematopoietic stem cells into differentiation pathways is accompanied by cell cycle arrest, irreversible differrentiation and apoptosis. A failure to respond to external stimuli regulating these processes within bone marrow micro-environment may lead to leukemias. Many years of studies on bone marrow and leukemia cells resulted in discoveries of various factors which regulate the differentiation processes from hematopoietic progenitors to adult blood cells, but processes which lead to leukemia development are still unclear.
Proteolytic enzymes regulate various processes in the human body, including hematopoiesis, blood clotting and fibrinolysis, and cancerogenesis. Many of these proteolytic enzymes are controlled by inhibitors from serpin (serine protease inhibitors) family. Today we know about 500 serpins, and 35 serpins are present in humans. The serpins are in general known as protease inhibitors, but the have also other functions which are not related to their inhibitory activity. We are interested in intracellular serpins which are expressed in hematopoietic progenitors. There is five intracellular serpins in bone marrow, but none of them has known function. Currently, we are studying bomapin that is hematopoietic-specific serpin expressed in hematopoietic progenitors (but not in the differentiated blood cells) and in leukocyte of patients with myeloid leukemia. We have recently shown that bomapin increases proliferation of myeloid leukemia cells and interacts in the cells with retinoblastoma protein. The retinoblastoma protein is one of the key regulator of cell proliferation and differentiation.
The aim of our studies is to search for role of bomapin in physiological hematopoiesis. Also, we want to find whether bomapin is important for leukemia development or leukemia progression. In general, our studies on the role of intracellular serpins should bring new knowledge on regulation of cell proliferation and differentiation during hematopoiesis. Since several serpins are markers for leukemia, it can not be excluded that they are involved in leukemia development or for invasive properties of leukemic cells. If this is the case, the intracellular serpins could be used as new targets for treatment of leukemia.
