Clinical and Pathogenetic Significance of Novel Biochemical Markers of Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a clonal disorder involving a multipotent hematopoietic progenitor cell. The disease is characterized by a stepwise progression with a terminal phase resembling acute leukemia. Despite substantial improvements in diagnosis and therapy the only curative treatment still is bone marrow transplantation. The pathogenetic hallmark of CML is the Philadelphia chromosome, i.e. the t(9;22) which is associated with the Bcr-Abl fusion gene. The product of the Bcr-Abl gene is directly involved in the pathologic function and growth of myeloid (progenitor) cells in CML. These cells differ from normal myeloid cells in many functional and phenotypic aspects. However, little is known about cellular antigens and mediators involved in disease progression. In fact, apart from the t(9;22) other genetic defects and cellular pathologies may contribute to the accelaration of CML and occurrence of blast crisis. One interesting aspect of CML is that during the acceleration of disease, an increase in basophils and basophil progenitor cells is frequently observed. Based on this notion we have recently started to analyze expression of basophil-related antigens in patients with CML. In these pilot experiments it was found that basophil-related markers such as histamine and CD203c can be utilized to monitor disease progression and the responses to specific therapies (Interferon; STI-571; bone marrow transplantation). Interestingly, these basophil-related antigens were found to be expressed not only in morphologically detectable blood basophils in these patients but also in immature agranular (basophil) progenitor cells. This observation highlights the superior value of these novel lineage- associated markers and raise the possibility that they may be related with the mechanisms of disease progression. The aims of the current project are to determine the prognostic value of biochemical basophil-markers in CML, to define the value of these markers in monitoring minimal residual CML by comparing with quantitative Bcr-Abl PCR and FISH, to examine the regulation of these markers, and to elucidate their pathophysiologic significance. The results of our project should improve our knowledge about the pathophysiology of CML and may help in defining novel useful markers to monitor CML patients during therapy.