Characterization of transplantable leukemic stem cells in CML and establishment of an improved xenotransplant model of CML

Chronic Myeloid Leukemia (CML) is a clonal malignant myeloproliferative disorder believed to originate in a single abnormal hematopoietic stem cell. The clinical course of CML can be divided into a "stable" or chronic phase and an advanced phase, covering both accelerated and blastic phase. Chronic phase CML lasts an average four to five years and may not cause serious disease symptoms. Untreated advanced phase CML patients die within a few weeks as a consequence of infection or bleeding. At present, the only curative option in CML is allogeneic bone marrow transplantation (BMT). However, only 20% of patients are eligible due to limitation in donor availability and/or advanced age. In patients without a compatible donor or those who are exceeding the age of 50 years, autologous BMT represents an alternative approach although cure rates are inferior in comparison to allogeneic BMT. Considerable improvement in our ability to identify the potential of human stem cells has been provided by the development of in vivo xenotransplant models. Most of the published studies report on the use of NOD/SCID mice as recipients of human hemopoietic cells. CML blood and marrow samples from newly diagnosed patients have been shown to be able to engraft NOD/SCID mice, although in most of the cases predominantly normal rather than leukemic hemopoiesis is obtained. I will characterize transplantable leukemic stem cells in CML and establish an improved xenotransplant model of CML. A considerable body of research has documented that tumor growth and metastasis require persistent new blood vessel growth. Bone marrow from patients with various hematologic malignancies contains a significantly increased density of microvessels. Recent studies report on the existence of a bone marrow-derived precursor endothelial cell which is a subset of CD34-positive cells and has the capacity to differentiate into endothelial cells upon increased angiogenic demand. We therefore will evaluate angiogenic activity in normal and leukemic hemopoietic grafts and study a retroviral vector-targeted antiangiogenic gene therapy model utilizing angiostatin and enclostatin cDNA.