Significance of tryptase production in myeloid leukemias

Research project P 14031 Significance of trytase production in myeloid leukemias Wolfgang R. SPERR 24.01.2000 Acute and chronic leukemias are life-threatening clonal disorders affecting a myeloid, lymphoid, or multipotent progenitor cell. These progenitors show a reduced ability of differentiation and maturation or/and a prolonged survival when compared with normal hemopoietic progenitors. During the past few years, substantial progress concerning the biochemistry and therapy of leukemias has been made. However, still, many questions related to the pathophysiology of leukemias remain open, and only a smaller percentage of patients is cured. For a number of human leukemias, more or less specific diseaserelated markers have been identified in the past. These markers are useful for determining the diagnosis and/or monitoring the course of disease and treatment response. Sometimes, even, minimal residual disease (= subclinical burden of neoplastic cells after therapy) is measurable by utilizing highly-sensitive, leukemia-specific markers. Also, such markers often are closely related to the pathophysiology or important fiinctional properties of leukemic cells. For a number of patients with leukemias, however, no disease- related markers are available at present. Therefore, leukemia research has been focusing on novel disease related (tumor) markers in recent years. Tryptases are trypsin-like serine proteases that show specificity for a limited number of substrates and are expressed in distinct leukocytes. Within normal hdmatopoiesis, tryptase is largely restricted in its expressed to mast cells. Basophils express only trace amounts of the enzyme and no significant amounts of tryptase are detectable in other leukocytes. Tryptases, exhibit a wide range ok biologic activities including mitogenic activity for various mesenchymal cells. Recent data have shown that cloned neoplastic, hematopoietic (myeloid) cells (= leukemia cell lines) express huge amounts of tryptase. Also, leukemic basophils, as opposed to normal blood basophils, express substantial quantities of tryptase. These observations prompted us to start a pilot project investigating tryptase expression in primary human leukemias, myelodysplastic syndromes (MDS = preleukemias), and myeloproliferative syndromes (NDS). Results of this pilot study show that indeed in a number of myeloid malignancies (proportion`of NMS, AML, and MPS), elevated serum and whole blood tryptase levels are detectable. It also was found that the elevated tryptase concentrations correlate with the burden of leukemic cells in these patients, and that indeed tryptase is produced by the myeloblasts (ANE). By contrast, lymphoid neoplasms appear to be tryptase-negative. The aims of this study are to analyze in detail the regulation and pathophysiologic role of tryptase expression in myeloid malignancies, and the clinical value of tryptase as novel disease-related marker. Results obtained in this project may thus improve our knowledge concerning the biochemistry and growth-regulation of ANE blasts and other myeloid malignancies. In addition, the project may also add a novel useful disease-related marker for leukemic patients in whom no other measurable parameters will become available.